The molecular details of coeliac disease

Australian, US and Dutch researchers have determined the molecular details of the interaction between the immune system and gluten that triggers coeliac disease. The study was led by Monash University in collaboration with colleagues from the University of Melbourne, Leiden University and ImmusanT, a company focused on restoring tolerance to gluten.

Coeliac disease is an immune system intolerance of gluten, a protein which occurs naturally in grains such as wheat, rye, barley and oats. The problem is that certain immune cells (T cells) regard gluten as a foreign and potentially toxic substance, and initiate action against it. The process is triggered when these T cells bind to gliadin, a component of gluten, triggering inflammation of the lining of the small intestine and giving many coeliac sufferers symptoms similar to food poisoning.

With the assistance of the Australian Synchrotron, the researchers isolated four different T cell receptors from coeliac individuals and captured their crystal structures during the central event in the disease: recognition of gluten peptides presented by the gene variant HLA-DQ2, which is associated with 90-95% of coeliac cases.

“This study allows us to visualise how T cells in patients with coeliac disease recognise the key component of wheat gluten that triggers coeliac disease,” said ImmusanT Chief Scientific Officer Dr Bob Anderson. “The results of this study demonstrate the target for ImmusanT’s approach to treating coeliac disease - the molecular interaction that links dietary gluten to a discrete population of T cells, which can bind precisely to certain gluten peptides.”

T cell receptor (space filling, on top) binds to the DQ2 molecule (ribbon and mesh).

The research will assist the development of a blood test and a therapeutic vaccine for patients with coeliac disease who carry the gene HLA-DQ2.5. ImmusanT’s Nexvax2 is such a product - a therapeutic vaccine designed to restore immune tolerance to gluten and allow patients to resume an unrestricted diet.

“Nexvax2, which is composed of peptides that bind to HLA-DQ2.5, targets gluten-specific T cells and reprograms them so that they act as allies instead of enemies, which means we are intervening right where the problem begins for patients at the molecular level,” said Leslie Williams, president and CEO of ImmusanT.

The research has been published in the journal Nature Structural and Molecular Biology