“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.”
Thus spoke Aretaeus of Cappadocia, a 1st-century AD Greek physician, describing distress in the “koelia”, or abdomen, and the sufferer’s accompanying inability to derive sustenance from food.
Many centuries of gastric distress later, during World War II, a Dutch paediatrician noticed that children with coeliac disease improved during bread shortages, but quickly deteriorated when Allied planes dropped bread. He was the first to pinpoint the disease’s definitive link to gluten, a protein complex found in wheat, rye and barley and oats.
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.”
Right now, coeliac patients have just one option to keep the train wreck at bay: cut gluten out of their diets completely. Patients who don’t comply are at risk of a whole host of problems down the road, including anaemia, osteoporosis, secondary autoimmune diseases such as type 1 diabetes, and intestinal cancers.
The problem, says Reid, is that it’s really hard to keep gluten out of your diet. “It’s in everything, especially processed foods. You only need to have a tiny little bit of contamination to damage the gut. It doesn’t always repair, and that’s the problem. Over time it gets worse.”
It’s important to distinguish coeliac disease from a food sensitivity, he adds. “If the genes for coeliac aren’t present, it’s not coeliac,” he says.
The interactions exposed in Reid’s x-ray crystallography studies have opened a possible treatment avenue. Out of the many different strings of amino acids produced when gluten is broken down in the gastrointestinal tract, we know that there are only a select few that are dominant in triggering the cascade of events leading to inflammation in coeliac patients.
That provides a possible window for intervention. “You could use vaccination to induce a state of tolerance,” he explains. “Exposing the immune system to a cocktail of these problematic gluten peptides through the skin trains the immune system to recognise them as harmless.”
If a patient had been "tolerised" in this way, the long, sticky strings of amino acids would not culminate in the unfortunate inflammatory response, because other T cells in the immune system, called T regulatory cells, would have been trained to quash the attack.
"You only need to have tiny little bit of contamination to damage the gut. It doesn’t always repair, and that’s the problem. Over time it gets worse.”
So perhaps one day people with coeliac disease will be able to have their cake and eat it, too. But Reid points out that there are still many unanswered questions about the disease.
The genes expressed by all coeliac patients are found in 20 to 30 per cent of the general population, yet only two to three per cent of those people have the disease. Nobody really knows why so many aren’t getting sick. We also don’t fully understand what triggers its onset, although there’s evidence it might be the fallout from an infection or a particularly stressful event.
“It’s a bit of a black box,” says Dr Reid. “There are many other genes and environmental factors associated with coeliac disease.”
Perhaps the most interesting mystery is why many coeliac patients produce highly similar T-cells that recognise these amino acid strings in the first place. It’s extraordinary, Dr Reid says, that people of different genetic backgrounds would all generate such similar T-cell receptor sequences. “We’re trying to understand the molecular basis of that,” he says.
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