“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