Day of Immunology
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Day of Immunology

Sharing our science with the community on the International Day of Immunology

“Somatic hypermutation”, “cluster of differentiation”, “antibody-dependent cellular cytotoxicity” – it’s another language scientists speak. Not a language that you normally hear around the dinner table or the supermarket or on the 6 o’clock news. But underneath that dense language are ideas and concepts that are key to understanding or improving our health - ideas that need to be shared.

Today, our access to information is unprecedented, and we can obtain a wealth of information on the causes of different diseases, symptoms, treatments, and risk factors. Getting the information is not the problem, but understanding the often dense language of science can be. To report the science accurately and to make sure it can be reproduced requires this type of precise and detailed language. So, scientists developed their own writing style. The downside to this style is that is not readily understood by non-scientists. From experience, I can tell you that it really does not work when trying to tell your grandma what you do for a living.

Thus, for the 2019 Day of Immunology, we wish to celebrate immunology by providing short summaries of recent publications from Immunology & Cell Biology that my grandma, Josephine Adele Bernier La Flamme, would appreciate and enjoy. Covering a wide range of topics from microbes in the gut to Tasmanian devils, editorial team members have prepared their own versions of recent articles as “Grandma Summaries.” Please enjoy and share with your own grandma.

Anne La Flamme, Immunology & Cell Biology Editor-in-Chief

Contagious Cancer – the curious case of Tasmanian devil facial tumour disease

Amanda Oliver & Jessica Borger

We all know that you can’t ‘catch’ cancer from another person, because cancer is not contagious. But, for Tasmanian devils this is not the case.

Contagious Cancer – the curious case of Tasmanian devil facial tumour disease

Amanda Oliver & Jessica Borger

We all know that you can’t ‘catch’ cancer from another person, because cancer is not contagious. But, for Tasmanian devils this is not the case.

Native to Tasmania, numbers of Tassie devils have been rapidly declining due to a puzzling type of cancer. Devil facial tumour disease or DFTD originated from a single devil who had developed a facial tumour that had formed from multiplying copies or clones of a single mutated nerve cell. The DFTD tumour cells were transmitted to other devils through open wounds inflicted during feeding and mating when devils savagely fight. Sadly, contracting DFTD is always fatal as painful tumours grow in and around the mouth, face and neck and become infected, leaving the devils unable to eat.

There has been a devastating effect on the numbers of wild Tassie devils, the main predator in Tasmania, since the identification of DFTD in 1996, creating a major environmental problem and costly establishment of conservation programmes. In order to save the wild Tassie devil populations from extinction, scientists have been researching ways to stop the transmission of this deadly disease and eliminate DFTD.

Recently, Gabriella Brown and her colleagues shared their research into DFTD in an article published in Immunology & Cell Biology. In order to understand what these scientists did, first it’s important to understand why it’s peculiar for a cancer to be contagious.

The immune system is designed to protect our body from attack by foreign invaders. To do this the cells in our body carry a unique combination of proteins called antigens. Similar to identifying fingerprints our immune cells can recognise these antigens as ‘self’ and safe. Self antigens are displayed on the surface of cells by a molecule called the major histocompatibility complex (MHC). Foreign invaders that enter our body including viruses, bacteria, microbes and even environmental pollutants are recognised as ‘non-self’ by our immune system as their fingerprints don’t match. When immune cells surveying our body don’t recognise the antigen presented by MHC, they enlist the recruitment of an army of killer T cells to go on the attack and shoot down the enemy with biological warfare. This explains why organ transplants or allografts between humans, who each have cells with their own fingerprints, are often rejected. In a similar way we would expect transmissible or transplanted DFTD allografts to be rejected. So why don’t the Tassie devils reject the tumour cells?

Devils and other marsupials have a similar immune system to humans but in the case of DFTD the killer T cells do not attack the DFTD tumour cells. One way DFTD tumour cells evade detection by the immune system is through camouflage by removing MHC from their surface. Without MHC on the surface of a tumour cell the killer T cells can’t identify the enemy and won’t mount an attack. Luckily, there is another battalion of killer cells, natural killer or NK cells, which search and destroy cells that don’t have any MHC. But in the curious case of DFTD, the Tassie devil’s NK cells fail to mount an attack.

In their study, Dr Brown and colleagues isolated NK cells from the blood of wild Tassie devils and mixed them with DFTD tumour cells in a dish. The DFTD tumour cells survived against the NK cells as they had failed to deploy their weaponry. So did this result mean there was a problem with the ability of the NK cells to seek and destroy?

To address this, 3 different drugs known to switch on NK cells and give them the instruction to attack were tested. When researchers added any one of these drugs to the Tassie devil NK cells to supercharge their killing abilities, they found that the DFTD cells were rapidly destroyed.

This promising result showed that the Tassie devil’s NK cells were fully functional and that instead the DFTD tumour cells have designed a clever evasion strategy to avoid detection or have found a way to overpower the NK cells. NK cells have proteins called inhibitory receptors, which like a brake on a car can be engaged by other cells to stop the killers in their tracks. The addition of any one of the drugs then may have acted like the accelerator pedal.

These fascinating results show that supercharging of NK cells, potentially through vaccination of the Tassie devils with the any of the drugs studied, will instruct the Tassie devil’s immune system to conquer and kill the DFTD tumour cells and one day restore the Tassie devil populations to their former glory.

Read the full article in Immunology & Cell Biology

Tackling the ingredients that trigger asthma in children

Simone Nuessing & Ian A. Parish

Australia has one of the highest asthma rates in the world, with Melbourne being called “the world’s allergy capital”.

Tackling the ingredients that trigger asthma in children

Simone Nuessing & Ian A. Parish

Australia has one of the highest asthma rates in the world, with Melbourne being called “the world’s allergy capital”. Asthma typically develops during childhood, but what causes some children to develop asthma while others do not? Do the genes we inherit from our parents cause asthma, or are factors in our environment the key triggers? A study by Fear and colleagues recently published in Immunology and Cell Biology suggests that the viruses we encounter as children may provide key ingredients that could cause asthma.

If we have a bug, our body is equipped with an immune system to fight off the infection. On occasion, this system “misfires”, and our body attacks something harmless, like pollen or house dust mites. Asthma occurs when our immune system over-reacts within our lungs to something harmless, such as pollen, that we breathe in from our environment. The results can be devastating, with the body’s immune reaction in the lungs making it hard to breathe.

A key question is if factors in our environment cause asthma. If these factors exist and were identified, perhaps we could develop new treatments to reduce asthma rates in children. Previous research has shown that childhood virus infections in the lungs are linked to an increased risk of asthma. Fear and colleagues aimed to pin down exactly what ingredients an infection provides that could cause asthma.

Infections cause many dramatic changes within our body to help fight off the invader. During infections with viruses, the body produces large amounts of molecules called “interferons”. Interferons signal to the body that a virus is in the neighbourhood, and help the body switch into “fight mode”. Fear and colleagues speculated that the changes in our body caused by exposure to interferons early in life might lead to an over-reaction to harmless factors that we breath in from our environment. This may then cause asthma in children. To test this idea, the researchers looked at whether giving interferons to young mice could cause an asthma-like reaction to a harmless chicken egg protein. They found that interferons caused an increase in the immune response to this harmless protein at many levels. Collectively, all of these changes summed up to an asthma response against something harmless that the immune system would normally ignore.

Therefore, when it comes to asthma, it’s not solely about our genes. Fear and colleagues were able to explain why there may be a link between recurring lung infections and asthma development in children. Interestingly, it is not the virus itself that may cause asthma, but it might instead be due to interferons, an ingredient from our own immune system.

Read the full article in Immunology & Cell Biology

Pregnancy and the Immune System

Tyani Chan

We all know that our immune systems play an amazing role at fighting off infections every day, without us even realising.

Pregnancy and the Immune System

Tyani Chan

We all know that our immune systems play an amazing role at fighting off infections every day, without us even realising. But did you know that our immune systems also play a big role in pregnancy?

When you stop and think about it, pregnancy is truly fascinating. A mum’s immune system, which is a well-oiled fighting machine constantly on the look out for anything that shouldn’t be there, suddenly has to deal with a growing baby that is only half mum, and half someone else. If an organ transplant only ‘half-matched’ it would be rapidly destroyed by the immune system – but intriguingly, this doesn’t happen in pregnancy.

Historically, immunologists wondered how a mum’s immune system could ‘tolerate’ a baby that had only half her DNA; in the first instance by allowing conception to even take place, then permitting the baby to exist, and finally investing her body’s resources to nurture the baby to full term. How does this happen? Was there a set of very specific and tightly controlled events taking place in order to achieve the purpose?

Yes, there are and immunologists have been working hard to figure out exactly what, when and how these events take place, and whether they might be misfiring in some women making conception difficult or who may experience early miscarriages.

Doctors Lachlan Moldenhauer and Kerrilyn Diener, and Professors John Hayball and Sarah Robertson from the Robinson Research Institute and Adelaide Medical School, The University of Adelaide, have recently made some exciting findings and chose to publish their cutting-edge work in Immunology & Cell Biology.

In a set of carefully controlled experiments, they mimicked normal and abnormal conditions in the uterus of mice during the very early stages of pregnancy when implantation is occurring. They discovered that the behaviour of a particular white blood cell can make the difference between pregnancy success or failure.

More specifically, they discovered that at the time when a fertilised egg is trying to attach to the wall of the uterus, cytokines (hormone-like molecules that talk to white blood cells) could either help or hinder early pregnancy success. This tells us that the immune cell environment in the uterus is extremely important at the earliest stages of pregnancy, because it can critically impact on whether a baby has the chance to grow to full term.

What does this mean and how does this help us? This exciting study points to how we should be looking deeper at the quality of the immune system around the time of conception, to better understand why some women experience miscarriage or fertility challenges.

Interested in reading more? Check out the full paper in Immunology & Cell Biology (2017), Volume 95, p 705, or contact us for a copy.

Read the full article in Immunology & Cell Biology

“It’s in our DNA” Genetics, gut microbes, and diabetes

Anne La Flamme

“It’s in our DNA” is now a common phrase. It suggests that certain traits are programmed in us.

“It’s in our DNA” Genetics, gut microbes, and diabetes

Anne La Flamme

“It’s in our DNA” is now a common phrase. It suggests that certain traits are programmed in us. These traits we have inherited from our parents through their genetic material or “DNA”.

Like eye colour or height, we inherit DNA that gives us a higher or lower risk for certain diseases like cancer, heart disease and diabetes. But, DNA is not everything. Instead, environmental factors such as diet, exercise, and smoking can modify that inherited risk.

A newly identified environmental factor is our microbiota – the microbes that live on and within us. Some “good” microbes protect us while others promote certain diseases. But which is stronger – DNA or microbes? That is the question that Jane Mullaney and her colleagues ask in a recent article published in Immunology & Cell Biology.

What is the relationship between DNA, microbes, and the development of autoimmunity (where the body’s immune system attacks oneself)? To answer this question, Dr Mullaney used mice that naturally develop an autoimmune disease (type 1 diabetes or “juvenile diabetes”) due to a genetic predisposition. Yes, it was in their DNA. She also had mice that were protected from disease and had very different gut microbes. The idea was to see if replacing the gut microbes in the disease-prone “high-risk” mouse with those from a protected mouse would be stop the development of diabetes.

At this point, you may be asking where we get these gut microbes. A good question. In fact, most of these microbes come from our mothers. We pick them up when we are born or during the first few weeks of life. Gut microbes can also change over time especially when we live closely with others.

So, Dr Mullaney tested if housing high-risk and protected young mice together would change their microbes. Surprisingly, she found that the gut microbes in the high-risk mice did not change. But, when high-risk mothers were housed with protected mice, their offspring did change to some extent. Also, she observed subtle changes to one immune cell type, a killer T cell, involved in juvenile diabetes. Both of these findings are encouraging.

The final question then is, can we stop diabetes if we give the high-risk mice the gut microbes that are like those of protected mice? In this instance, the microbes that were good for the protected mice could not overcome the genetic predisposition of the high-risk mice. It was just too strong. It was in their DNA.

Read the full article in Immunology & Cell Biology

Infant immunosuppression - protecting the innocent from themselves

Kayla Wilson & Justine D. Mintern

After spending nine months developing in the safe environment of a mother’s womb, babies are suddenly pushed into a hostile world of bacteria, fungi and parasites.

Infant immunosuppression - protecting the innocent from themselves

Kayla Wilson & Justine D. Mintern

Parson et al. Murine myeloid-derived suppressor cells are a source of elevated levels of interleukin-27 in early life and compromise control of bacterial infection. Immunology and Cell Biology, 2018

After spending nine months developing in the safe environment of a mother’s womb, babies are suddenly pushed into a hostile world of bacteria, fungi and parasites. Their immune system is kicked into overdrive. Over time, exposure to pathogens, along with vaccinations, ensures better protection against foreign threats, however in their first months, babies are vulnerable. So vulnerable, in fact, that every single day in 2017, 7000 babies died in their first month of life (World Health Organisation). The majority of these deaths were due to an increased susceptibility to infectious diseases. What causes this susceptibility and is there anything we can do to prevent it?

In the hopes of finding a better way to protect babies, scientists have been investigating the intricacies of infants’ immune systems. They have found that infant immune cells simply don’t function as well as their adult counterparts. One possibility for this is that the immune cells need to mature before being conscripted into our immune system army. Another possibility is that the immune cells are ready for combat but are held back by other factors. This is known as immune suppression and is thought to protect the baby and mother during pregnancy. In a recent article published in Immunology & Cell Biology, Madeline Parson and colleagues asked what factors could be causing infant immune suppression.

During an infection, many different immune cells from all over the body have to work together to protect us from foreign invaders. This immune response is orchestrated by signalling molecules which tell the immune cells where to go and what to do. Parson and colleagues found that young infants have increased levels of a specific signalling molecule called interleukin 27 (IL-27). As far as signalling molecules go, IL-27 is notorious for immune suppression, but where does it come from in infants?

To answer this question, the researchers turned their attention to a small group of immune cells called myeloid-derived suppressor cells (MDSCs). While these cells aren’t usually found in healthy people, they do pop up when adults are sick for prolonged periods of time. Interestingly, Parson and colleagues identified MSDCs as being very abundant in infants. Furthermore, they showed these cells produce IL-27 along with other factors known to cause immune suppression. Importantly, when different immune cells were placed with the MSDCs they could no longer perform their function. The researchers showed that the MSDCs were indeed immune suppressive and that this was due, at least in part, to their production of IL-27.

Understanding the complexities of infant immunity is critical to better protecting infants. The data presented by Parson and colleagues demonstrates that the early days of life are characterised by lots of suppressive cells (MSDCs) and suppressive signalling molecules (IL-27), which together fight to shut down immunity. The next big question is how we can remove these suppressive mechanisms to better protect infants from infection.

Read the full article in Immunology & Cell Biology

Dysfunctional defence causes severe flu infections in infants

Annabelle Blum & Justine D. Mintern

Influenza, more commonly known as “flu” is a virus that infects millions of people every year causing fevers, headaches, coughing and sneezing.

Dysfunctional defence causes severe flu infections in infants

Annabelle Blum & Justine D. Mintern

Verhoeven and Perry. Differential mucosal IL-10-induced immunoregulation of innate immune responses occurs in influenza infected infants/toddlers and adults. Immunology and Cell Biology, 2017.

Influenza, more commonly known as “flu” is a virus that infects millions of people every year causing fevers, headaches, coughing and sneezing. Enclosed in tiny air-droplets flu can spread rapidly provoking yearly seasonal epidemics. A healthy adult can recover from flu infection and be back on their feet within a couple of weeks. In contrast, children, elderly and chronically ill people suffer more severe flu infections that can require hospitalisation and even lead to death. Numbers published by the World Health Organisation show that approximately half a million people die from flu worldwide every year. This is a large number of avoidable deaths given the widely available flu vaccines. Children are at risk of severe flu infection however, as their immune systems differ from adults.

In an article published in Immunology & Cell Biology David Verhoeven and Sheldon Perry investigated how an infant’s immune response acts to eliminate flu infection. The questions they asked were: why do children show such poor immune responses to flu? Why is the immune response to flu in children inferior to that of adults?

The study dissected different parameters of the infant flu immune response. It showed that the young immune response has a major impairment in T cells. These cells can be described as the soldiers of the immune response, whose job it is to seek out and destroy flu-infected cells. Verhoeven and Perry also described a dysregulation in immune signalling molecule (interleukin 10) and the cells that release it. Signalling molecules are critical to control the actions of the T cell army. Due to these failings in the infant immune response, the flu virus exhibited prolonged growth and its clearance from the infants was delayed. This results in infants suffering longer and more severe flu infections.

The study by Verhoeven and Perry is important because it helps us explain the major defects involved in the infant immune response to flu. It takes us a step towards understanding why children are more at risk of suffering severe illness in response to this potentially deadly virus. The outcomes of this research identify immune cells and molecules that can be targeted clinically to boost immune responses to flu infection in children.

Read the full article in Immunology & Cell Biology

Dealing with dead cells in systemic sclerosis

Jurie Tashkandi, Yang Huang & James Harris, Monash University

In any given day, it is estimated that 50-70 billion cells die within the human body.

Dealing with dead cells in systemic sclerosis

Jurie Tashkandi, Yang Huang & James Harris, Monash University

In any given day, it is estimated that 50-70 billion cells die within the human body. After cells have performed their function, they are no longer needed and are destined to die through a natural process called apoptosis. During apoptosis, the cell dies in a tightly controlled way. In particular, the cells carefully wrap up anything that might be potentially dangerous (e.g. toxic and/or inflammatory) if it were released. In addition, the cell helpfully covers itself in “find me and eat me” signals, molecules that enable other cells to track them down and, literally, eat them. These cells include macrophages, so-called professional phagocytic cells (cells that are very good at eating stuff) and the process of eating dead cells is called efferocytosis.

Systemic sclerosis (SSc or “scleroderma”) is a rare, chronic autoimmune disorder characterised by inflammation and fibrosis of the skin, lungs and other organs. Fibrosis is the build-up of scar tissue, which in the case of scleroderma is due to overproduction of collagen – a tough protein whose job is to strengthen connective tissues in the body, such as tendons, skin and ligaments. This causes thickening of the skin (In Greek, sclero means “hard” and derma means “skin”). However, as the name systemic sclerosis implies, thickening of tissues all over the body also occurs, leading to damage of internal organs, including lungs, heart and kidneys. For reasons we don’t yet understand, SSc is more prevalent in women and is both highly debilitating and life threatening.

Many autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE or just “lupus”) and SSc are characterised by the presence of autoantibodies; antibodies that target our own proteins. Normally, antibodies are produced against foreign invaders, such as bacteria, viruses and fungi (antibodies are what vaccines induce and these are protective against those diseases). Antibodies stick to those invaders, making them easier targets for immune cells to deal with (kill). However, sometimes they can also target host cell proteins. In SSc, it is common to find autoantibodies that target cell components normally found tucked away in the nucleus. It is thought that inefficient clearance of dead cells could be a key factor in the production of autoantibodies.

When dead cells are not cleared away quickly enough they can effectively start to burst open (a process called necrosis) and release intracellular molecules, including some that cause inflammation, alongside nuclear proteins. This combination can lead to the activation of multiple immune cells, including those involved in antibody production, and ultimately lead to the production of autoantibodies. These antibodies can then attack the hosts own cells and tissues, leading to further inflammation and organ damage. Think of macrophages as garbage removal trucks – if they break down and stop doing their job, the neighbourhood becomes overrun with garbage, which becomes disruptive and dangerous.

Sometimes, phagocytic cells, particularly macrophages, may not be as good at efferocytosis as they should be, perhaps due to inherent genetic defects, or as a result of specific disease-related conditions. A recent study Ballerie et al1, sought to determine whether macrophages from patients with SSc have a reduced capacity for efferocytosis. Comparing macrophages from SSc patients and healthy controls grown in the lab, they found that the macrophages from the SSc patients were significantly less effective at eating apoptotic cells, suggesting they had inherently defective efferocytosis. This, in turn, could lead to a build-up of dead cells. They went on to show that part of the reason for this is that those macrophages express less of a certain receptor (a molecule that recognises one of the “find me” signals on dead cells), called ITGβ5, than those from healthy donors. Other receptors that they thought might be involved in fact were not, further suggesting a very specific defect in the garbage disposal cells of SSc patients.

And that is where this part of the story ends. In the movies, scientific research is usually portrayed in the context of huge, paradigm-shifting discoveries that save the world from some impending disaster (usually the result of some monkey-borne outbreak or, more likely, some mad scientist unleashing unholy terror on the world). In reality, science is rarely (almost never) anything like that. Instead, it is a series of small, incremental (but very important) advances in our understanding. The “big” discoveries are often the culmination of a lot of little discoveries. This study tells us that a specific defect in macrophages might be important in the development, or pathology, of SSc. However, we don’t yet know for sure if this is the case. That requires further work. But, if it is, then we may have the beginnings of a new treatment strategy/target. However, this study does tell us a little bit more about the biology underlying one aspect of this terrible disease and that is one step forward in understanding how it all works and how we might utilise that for the benefit of patients. And that really is important.

References

1. Ballerie A, Lescoat A, Augagneur Y, Lelong M, Morzadec C, Cazalets C et al. Efferocytosis capacities of blood monocyte-derived macrophages in systemic sclerosis. Immunol Cell Biol 2019; 97(3): 340-347.

About the authors

Jurie Tashkandi and Yang Huang are 3rd year undergraduate Biomedical Science students at Monash University. James Harris is Head of Laboratory Research for the Rheumatology Group at Monash University and Deputy Editor for.