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Coeliac disease specific antigen found

Abi Berger BMJ

The discovery of a coeliac disease specific antigen could offer a new route for treatment of the condition. Dr Robert Anderson and his colleagues at the Institute of Molecular Medicine in Oxford have identified a peptide in wheat that elicits a specific immune response in people with coeliac disease.

If this immune response could be blocked, then the need to stick to a gluten free diet could become obsolete (Nature Medicine 2000;6:337-42).

Dr Anderson, a gastroenterologist, and his team set out to find the toxic part of the gluten molecule. It is already known that gluten can be separated into three fractions, and that the toxic part of the molecule is probably contained in the alpha-gliadins fraction.

All gliadins are similar in structure, although one in particular (A-gliadin) has been well characterised. Dr Anderson synthesised the 51 overlapping peptides that span the complete sequence of this gliadin and treated each with transglutaminase.

This is the enzyme that is recognised in the antiendomysial antibody test for untreated coeliac disease, and it is known that gliadin specific lymphocytes respond much more vigorously to gliadin treated with transglutaminase than to native gliadin.

Dr Anderson's team then took 12 patients with coeliac disease whose condition was stable on a gluten free diet and asked them to eat four slices of bread every day for three days. Blood tests taken before and after the bread challenge showed that only two of the 51 gliadin peptides had stimulated an immune response. These two peptides overlapped each other, and seemed to require treatment with transglutaminase to be active. The specific lymphocytes that had been induced by these peptides appeared in the blood 6-8 days after the gluten challenge.

The researchers then showed that a single peptide could account for the immune response induced against A-gliadin and that transglutaminase treatment converted a single glutamine amino acid in this peptide to glutamate. To see if it was this specific conversion that was responsible for the activity of the peptide, Dr Anderson synthesised the same peptide with glutamate replacing the specific glutamine. He found an exact correlation between the activity of the peptide modified by transglutaminase and the synthetic peptide.

"It's the first time that a specific peptide has been identified in patients with coeliac disease by directly sampling blood after a gluten challenge," said Dr Anderson. "We were also surprised that the early immune response in coeliac disease picks out only one peptide, and then only after it has been modified by an intestinal enzyme."

The team compared four controls (HLA matched subjects with no known coeliac disease) with their 12 coeliac patients. The controls were put on a gluten free diet for four weeks and then challenged with bread for three days. None of the controls mounted the immune response seen in the coeliac patients. This work suggests that if a way can be found to block the immune reaction to the coeliac disease specific antigen, then people with coeliac disease may be able to revert to an unrestricted diet.