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Our new research collaboration with Janssen to tackle coeliac disease

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Monash University has signed a multi-year research collaboration with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to advance the understanding of the immune mechanisms underpinning Coeliac Disease and inform the development of new methods of diagnosis and treatment. The research will be led by Professor Jamie Rossjohn from the Monash Biomedicine Discovery Institute. The collaboration was facilitated by Monash Innovation, part of the Enterprise portfolio at Monash University, and by Johnson & Johnson Innovation LLC.

Coeliac Disease is a serious health condition affecting approximately 1 percent of the world’s population. It occurs when dietary gluten (a food protein found in wheat, rye, barley and oats) triggers a damaging immune response that attacks the body. Coeliac disease is associated with a range of health problems and often causes digestive symptoms such as bloating, abdominal pain and diarrhoea. It can also cause anaemia, low iron levels and excessive tiredness and is associated with osteoporosis, other autoimmune disease, infection and some types of cancer.

Providing a definitive diagnosis to Coeliac Disease currently entails invasive biopsy and improved diagnostics and better treatments are urgently needed. Presently, the only approved treatment is a gluten-free diet; there is no known cure. With the disease affecting on average approximately 1 in 70 Australians with around 80 percent of this number undiagnosed, the vast majority of Australians who have coeliac disease are unaware they have it.

Deputy Vice-Chancellor (Enterprise), Professor Ken Sloan, said the research agreement with Janssen is another example of Monash actively engaging with industry to explore new avenues: “Monash University remains committed to moving research forward for the betterment of human health, creating new avenues and opportunities that may lead to tangible benefits for the broader community”, Professor Sloan said.

Director of the Monash Biomedicine Discovery Institute, Professor John Carroll, said the collaboration brings together leading researchers and industry partners to tackle this major health issue that affects so many individuals around the world.

“This collaboration is another example of how Monash BDI’s strong clinical relationships and industry engagement aim to accelerate the development of diagnostic and preventative treatments,” Professor Carroll said.

Professor Rossjohn stated: “The team at Monash, including Dr. Hugh Reid, Prof Nicole La Gruta and Prof. Tony Purcell, look forward to working alongside Janssen colleagues to develop innovative immunotherapeutics to prevent and treat Coeliac Disease.”

Original article

Our recent coeliac disease research featured in the Age

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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

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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

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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.

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Could people living with coeliac disease one day be able to have their cake and eat it, too?

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“If the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons coeliacs.”

Although coeliac disease is fairly common, affecting about one in 70 people of European descent, it’s still challenging to diagnose and treat. It’s best known for its classic digestive symptoms – diarrhoea and bloating — but it can also manifest in neurological conditions, skin rashes, osteoporosis, infertility and anaemia, or sometimes nothing at all. Children experience failure to thrive, delayed puberty, cognitive and behavioural issues and tooth enamel problems.

“It has such a broad spectrum of symptoms that some people don’t even know they have it,” says Dr Hugh Reid, who’s studying coeliac with his team in the Infection and Immunity group in Monash’s Biomedicine Discovery Institute. “Gastroenterologists think it’s very much underdiagnosed.”

Using the Australian Synchrotron facility, Dr Reid and his team look at how individual protein molecules behave when a coeliac patient ingests gluten. “It’s basically a train wreck.”

First off, gluten contains the amino acid proline. Enzymes in the gastrointestinal tract that break strings of amino acids into smaller fragments, or peptides, can’t chop up proline-heavy proteins very well. “Instead of peptides of just one to a few amino acids long, you can get up to 10 to 20 amino acids on that fragment,” says Reid.

Another thing all coeliac patients have in common is an increased amount of an enzyme called transglutinase 2 (TG2). It transforms one of these amino acids into a version that’s negatively charged, effectively making it “sticky”.

These sticky strings then bind to HLA molecules, specialised protein complexes embedded in the outer surface of our cells. They perform the critical task of scooping up protein fragments and presenting them to T-cells, the roving border patrol of the immune system.

If the receptors on the surface of a T-cell mesh with a peptide on an HLA molecule in just the right way, an alarm goes out and the troops are called in. This is how the immune system distinguishes self from non-self, harmless proteins in food from dangerous bits of bacteria. It’s a complicated system that works astonishingly well – most of the time.

Because there are so many possible combinations of the 20 amino acids, we produce many different HLA molecules to present peptides and many different specialised T-cells to recognise them. Coeliac patients have been dealt a rotten hand here – they have genes that produce one or two HLA versions with a particular affinity for these specific long, sticky strings of gluten residues.

Then, one of their T-cells mistakenly recognises this particular peptide presentation as being harmful, and unleashes a massive inflammatory response that damages the lining of the intestine and produces autoantibodies that can go on to attack other organ systems.

“The thing that makes this extraordinary is that this [peptide presentation] just happens to be the lock that this [T-cell receptor] key fits,” says Reid. “It’s just terribly bad luck.”

Original article