Triggers for coeliac disease 'found'

“The precise cause of the immune reaction that leads to coeliac disease has been discovered,” BBC News reported. It said that three key substances in gluten have been found to trigger the condition, and researchers believe them to be a potential new target for developing treatments and possibly a vaccine.

These researchers asked 200 volunteers with coeliac disease to eat bread, rye muffins or boiled barley, all of which contained gluten. They then measured the volunteers’ immune response to thousands of different peptides (gluten fragments) six days later. Among 90 possible peptides, three were found to be particularly toxic.

This research appears to have been carefully carried out and is well reported. These are important findings and show some promise in the search for a treatment for coeliac disease. Early clinical trials are reportedly already underway, testing whether a compound containing these three peptides can stimulate an immune reaction. The full implications will not be known until after these trials are complete.

Where did the story come from?

The study was carried out by researchers from Australia, the UK and Italy. It was partly funded by the National Health and Medical Research Council (NHMRC), the Coeliac Research Fund in Australia and several other institutions in Europe. The study was published in the peer-reviewed journal Science Translational Medicine.

Both the Daily Mail and the BBC accurately reported the main details and implications of this complex laboratory study.

What kind of research was this?

Coeliac disease is a common digestive condition in which a person is intolerant (has an adverse reaction) to gluten, a protein present in wheat, barley and rye, and which can be found in pasta, cakes and most types of bread. People with the condition can have a wide range of symptoms when exposed to gluten, including diarrhoea, bloating and abdominal pain, and the severity of the symptoms can range from very mild to severe.

These symptoms are caused by the immune system mistaking gluten for a hostile organism, such as a virus. The immune system attacks the gluten, which can lead to the small intestine becoming damaged.

The researchers explain that the response of CD4+ T cells to gluten is what initially causes the immune response. The T cells are triggered when they encounter the peptides (simple chemical compounds) derived from gluten. Identifying the type of peptides that cause the greatest immune response (known as epitopes) may aid the development of new treatments. One such potential treatment is immunotherapy, where the body is repeatedly exposed to the toxins that cause the immune response, eventually making the body accustomed to them. The researchers say this method has reportedly been successful in mouse models of diseases caused by T cells.

The laboratory research was complex, but does appear to have shown a clear direction for future research. The researchers say that a peptide-based immunotherapy can be designed and tested for this condition and that the lead compound (the three immunogenic gluten peptides) is now in phase I clinical trials.

What did the research involve?

The researchers recruited 226 volunteers with coeliac disease from Oxford and Melbourne. The average age of the volunteers was 50 years and 73% were women. A control group of healthy volunteers of a similar age was also selected.

The participants were asked to take part in a number of ‘oral grain challenges’, in which they ate slices of wheat bread, barley risotto, rye muffins or a combination of these over three days. People with coeliac disease took part in 226 of these challenges, and the healthy volunteers took part in 10.
Overall, 113 challenges tested wheat, 41 tested barley, 43 tested rye and 29 tested all three grains combined. It is not clear if each volunteer was tested with more than one grain.

At the time of the challenge, the volunteers with coeliac disease had been strictly gluten-free for three months or more, and the healthy volunteers for four weeks. The challenges were designed to induce an immune response in the volunteers, where their bodies produced gluten-specific T cells. The researchers then analysed these cells from blood samples to identify which peptides they could recognise.

At the start of the study and after six days, blood was taken for analysis, with the total volume collected on both occasions not exceeding 300ml.

What were the basic results?

The blood samples showed that particular cereals and grains resulted in the specific peptides which then stimulated the T cells. Three peptides for the three grain/cereal types.

However, when they looked at the challenge when all grains were taken together, a specific sequence from peptides found in wheat and barley seemed to be the main epitope responsible for the immune response. This meant they thought these two were “dominant” regardless of the grain consumed.
The researchers also say that just three peptides accounted for most of the T cells that responded to gluten ingestion and that once these were taken into account other gluten peptides became less important.

How did the researchers interpret the results?

The researchers say that their findings show that T cells, a cause of coeliac disease, are similar in terms of the peptides they recognise and therefore a peptide-based therapy for this disease should be possible.