Our recent coeliac disease research featured in the Age

Coeliac disease linked to bacteria exposure

The Age article by Liam Mannix. Original article

Exposure to bacteria that mimics gluten can confuse the immune system and trigger coeliac disease, Melbourne scientists have shown for the first time.

The results raise the possibility of using probiotics or developing a vaccine to prevent the disease, which affects nearly 400,000 Australians.

Some of the suspect bacteria lives naturally in our guts – which might explain why people with coeliac disease can still suffer even after eliminating gluten from their diet.

“This is the first time we have shown a potential mechanism for why the microbiome may be involved in the initiation of this disease,” says Hugh Reid, the Monash University researcher who led the multi-institute study.

The study also has big-picture implications. If bacteria have proteins that mimic gluten, they probably have proteins that mimic lots of things people are allergic to. Could it be that bacteria and viruses trigger many common autoimmune conditions?

Molecular mimics

Coeliac disease occurs when the body’s immune system begins reacting to gluten, a protein found in wheat, rye and barley.

When someone with the disease eats gluten, their immune system misidentifies it as a foreign invader. It mounts a huge immune response in the gut, trying to “kill” the gluten – which can lead to bloating, diarrhoea and intestinal damage.

About 50 per cent of people carry the genes that make them susceptible to coeliac disease, but these people are not born allergic to gluten. Only one in 70 with the genes ever develops it.

It seems they come across some sort of trigger as children, activating the condition before their immune system has fully matured. Scientists have long suspected mimics are to blame.

A small number of viruses and bacteria produce protein fragments that look almost identical to parts of gluten – “molecular mimics”, scientists call them.

The team used molecular databases to assemble a set of protein fragments produced by bacteria that looked near-identical to gluten. They ended up with about 20, many produced by species that live naturally – and harmlessly – within our gut.

Then researchers at the Walter and Eliza Hall Institute took blood from people with coeliac disease, and exposed the immune cells to the gluten mimics the team had found.

Immediately, the immune cells went on the attack – just like if they had spotted a molecule of gluten. “It’s a case of mistaken identity,” says Dr Reid.

To confirm the results, they used the Synchrotron, a 200-metre-long tube buried under the Melbourne suburb of Clayton that shoots out light 1 million times brighter than the sun, to take a high-resolution molecular photograph of the bacterial protein fragments as they reacted with immune system molecules.

The images looked identical to the way the gluten fragments reacted with the same molecules. “That nailed it,” says Dr Reid.

The smoking gun

The team’s paper, published in Nature Structural and Molecular Biology, is the smoking gun for the molecular mimic theory, but there are lots of questions still to be answered.

The big one: if these mimic-bacteria live in many people’s guts, why doesn’t everyone with susceptible genes get coeliac disease?

The answer may have to do with the number of bacteria, Dr Reid says.

The immune system might happily tolerate a small number of mimic bacteria living in our guts. But if there are too many, it might go on the attack.

It might then remember that attack – our immune systems are designed to remember viruses and bacteria they come across – and mount an offensive whenever it sees a similar molecule. Like gluten.

That would explain why studies have shown children who develop coeliac disease tend to have abnormal microbiomes.

Using antibiotics, which kill off healthy gut bugs and open space for other ones to thrive, is also linked to developing coeliac disease.

Perhaps this allows the number of mimic bacteria to grow high enough to trigger the disease?

“There are a lot of questions that are not answered by this,” says Dr Reid. “But we have paved the way for developing strategies for preventing this disease.

“We could vaccinate people against this particular bacteria, potentially, or use probiotics.”

Hugh on Channel 9 news speaking about our latest paper on coeliac disease

Researchers are a step closer to finding what causes the debilitating coeliac disease, which affects around one in 70 Australians.

Read the press release here.

Read the publication in Nature Structural & Molecular Biology here.

 

Bacterial link in coeliac disease

Bacterial exposure has been identified as a potential environmental risk factor in developing coeliac disease, a hereditary autoimmune-like condition that affects about one in 70 Australians.

It is estimated that half of all Australians are born with one of two genes that cause coeliac disease, and approximately one in 40 are likely to develop the condition. People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems.

While environmental factors are known to trigger Coeliac Disease in those with the genetic predisposition, exactly how that works has remained unclear.

Scientists from the Monash Biomedicine Discovery Institute (BDI) and ARC Centre of Excellence in Advanced Molecular Imaging, have now provided a molecular foundation for microbial exposure as a potential environmental factor in the development of coeliac disease.

The results of the study, done in collaboration with researchers at Leiden University Medical Centre and the Walter and Eliza Hall Institute of Medical Research, have been published in the journal Nature Structural and Molecular Biology.

Co-Lead researcher Dr Hugh Reid, from Monash University, said the team showed, at the molecular level, how receptors isolated from immune T cells from coeliac disease patients can recognise protein fragments from certain bacteria that mimic those fragments from gluten.

Exposure to such bacterial proteins may be involved in the generation of aberrant recognition of gluten by these same T cells when susceptible individuals eat cereals containing gluten, he said.

“In coeliac disease you get aberrant reactivity to gluten and we have provided a proof-of-principle that there’s a link between gluten proteins and proteins that are found in some bacteria,” he said.

“That is, it’s possible that the immune system reacts to the bacterial proteins in a normal immune response and in so doing develops a reaction to gluten proteins because, to the immune system, they look indistinguishable – like a mimic.”

Dr Reid said the findings could eventually lead to diagnostic or therapeutic approaches to coeliac disease.

About coeliac disease

Coeliac disease is caused by an aberrant reaction of the immune system to gluten, a protein which occurs naturally in grains such as wheat, rye, barley and oats, and therefore is typically found in bread, pastries and cakes. Immune system cells, known as T cells, regard gluten as a foreign substance, and initiate action against it. In patients with CD, activation of these T cells leads to an inflammatory response in the small intestine causing a wide range of symptoms including diarrhoea, bloating and malabsorption of nutrients, to name a few.

People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems.  If left untreated, the disease can cause serious issues including malnutrition, osteoporosis, depression and infertility, and there is a small increased risk of certain forms of cancer, such as lymphoma of the small bowel.

Image: “Mimicry”. Artwork depicting the way bacterial proteins mimic gluten proteins, causing an immune response to coeliac disease. Artwork by Dr Erica Tandori.

Original article

Discovery shines light on the cause of some allergic responses

A team of international researchers from Monash University, Columbia University and Harvard Medical School has discovered how some compounds contained in cosmetic and perfume products can activate human T cells, the sentinels of our immune system.

It’s long been known that certain chemicals cause allergic contact dermatitis (ACD), but our understanding of why this is happening is still very limited.

The teams led by Monash University’s Professor Jamie Rossjohn, Dr Annemieke de Jong from Columbia University and Harvard Medical School’s Dr Branch Moody investigated the role a common protein in the skin – known as CD1a – could play in allergic reactions to cosmetics.

Researchers found more than a dozen small compounds that were able to associate with the CD1a protein leading to an immune response in human T cell culture.

“Normally, many CD1a molecules are filled with natural blockers in our bodies that would prevent an exaggerated immune response, and those small compounds basically remove those natural blockers” says Dr Marcin Wegrecki, who together with Dr Jerome Le Nours, was part of the Monash University team involved in the study.

Part of the research focused on small chemicals found in many essential oils and botanical extracts such as the Balsam of Peru, an oily tree resin found in many cosmetic products, toothpastes and fragrances.

“Balsam of Peru was also used in natural products because it comes from a tree – it’s not chemically synthesised – so it was very popular. But unfortunately a significant number of people – up to five per cent of the population – is allergic to it because it contains all those small compounds,” he said.

Using a high energy X-ray beam at the Australian Synchrotron at Monash University, the researchers were able to describe the way CD1a and farnesol, another common additive in cosmetics and skin creams, interact at a molecular level.

Dr Wegrecki, of the Monash Biomedicine Discovery Institute, said the results, published in Science Immunology, gave more clarity around what was happening. “Now we know how some of the compounds found in skin care products and cosmetics can directly interact with human proteins,” he said.

Despite the known allergy, Balsam of Peru is still used in some products, including toothpaste, sunscreen, face creams and cosmetics.

Further research into the clinical significance of these molecular findings could now help scientists understand how those small chemicals induce ACD and potentially design strategies to revert their allergenic effect.

Image: “Allergens and cosmetics”. Artwork of a moisturiser jar containing a depiction of the immune molecule, CD1a, binding to the allergic compound. Artwork by Erica Tandori, Artist in residence from the Rossjohn lab at Monash University.

Original article

Advanced imaging tips T cell target recognition on its head

T cells represent a key component of our immune system, and play a critical role in protecting us against harmful pathogens like viruses and bacteria, and cancers. The more we understand about how they recognise, interact with and even kill infected or cancer cells moves us closer to developing therapies and treatments for a range of conditions.

In a paper published today in the premier international journal Science, an Australian team of scientists led by Monash University, the Australian Research Council Centre of Excellence in Advanced Molecular Imaging and the University of Melbourne at the Doherty Institute, has redefined what we thought we knew about T cell recognition for the past 20 years.

In order to interact with other cells in the body, T cells rely on specialised receptors known as T cell receptors that recognise virus or bacteria fragments that are bound to specialised molecules called major histocompatibility complex (MHC) or MHC-like. Over the past 20 years, the prevailing view was that T cell receptor sat atop the MHC and MHC-like molecules for recognition.

The team of scientists characterised a new population within a poorly understood class of T cells called gamma delta T cells that can recognise an MHC-like molecule known as MR1. Using a high intensity X-ray beam at the Australian Synchrotron, the scientists obtained a detailed 3D image of the interplay between the gamma delta T cell receptor and MR1 revealing an intriguing result whereby the gamma delta T cell receptor bound underneath the MHC-like molecule for recognition. This highly unusual recognition mechanism reshapes our understanding of how T cell receptors can interact with their target molecules, and represents a major development in the field of T cell biology.

“Think of it like a flag attached to a cell. We always thought the T cells were coming along and reading that flag by sitting atop it. We have determined that instead, some T cells can approach and interact with it from underneath,” said Dr Jérôme Le Nours from the Monash Biomedicine Discovery Institute, co-lead author on the paper.

“These are the types of fine and important details that can change how we approach future research avenues in T cell biology,” said Dr Le Nours.

“This is important because T cells are a critical weapon in our immune system, and understanding how they target and interact with cells is crucial to harnessing their power in therapies such as infection and cancer immunotherapy,” he said.

”Our study shows that MR1 is a new type of molecular target for gamma delta T cells. These cells play a decisive role in immunity to infection and cancer, yet what they respond to is poorly understood. MR1 may be signalling to gamma detla T cells that there is a virus, or cancer cell and triggering these cells to initiate a protective immune response,” said Dr Nicholas Gherardin from the Doherty Institute, co-lead author on the paper.

“We’re very excited to follow up these findings in studies that will aim to harness this new biology in disease settings,” he said.

The research findings were a culmination of a six-year project that involved collaborative support from Australian scientists, the ARC Centre of Excellence in Advanced Molecular Imaging, the use of the Australian Synchrotron, and funding from the National Health and Medical Research Council and the Australian Research Council.

Read the full paper in Science titled A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1.

Image: Artwork of a gamma delta T cell receptor interacting with MR1.  Artwork by Dr Erica Tandori.

 

Original article