Another brick in the coeliac wall
New research has added another brick to the wall in discovering the immune triggers for coeliac disease. Monash Biomedicine Discovery Institute scientists, who are also members of the Australian Research Council's Centre of Excellence for Advanced Molecular Imaging, Dr Hugh Reid and Dr Jan Petersen have been working on imaging and figuring out the mechanisms of coeliac disease for more than six years. Their recent findings provide a framework for designing drugs to interfere with our immune system which, in the future, will hopefully offer coeliac disease sufferers some relief.
When individuals ingest wheat rye and barley, the gluten protein from these grains is incompletely broken down into short peptide fragments. In coeliac disease, these peptides are post translationally modified in such a way that they become more “sticky” so that they bind more strongly to human leukocyte antigen (HLA) molecules that present these peptides to the sentinels of the immune system, the T lymphocytes – aka: T cells.
Receptors on the surface of T cells known as T cell receptors (TCRs), recognise these gluten peptides bound to these HLA molecules and then trigger the T cells to mount an attack against the gluten peptide. This leads to a strong inflammatory response in the gut which in turn damages to the microvilli (structures of the gut responsible for nutrient adsorption) and the symptoms of the disease (diarrhoea, nausea, constipation and vomiting).
The immune cell invasion of the gut occurs because the immune system has mistakenly detected a threat and mounts a response to a harmless food protein. In normal patients, T cells and their TCRs evolve to detect peptides generated from microbial pathogens so as to only generate an attack when presented with the threat of infection.
Work done in the Imaging CoE’s Rossjohn laboratory, at the Monash Biomedicine Discovery Institute, has previously shown that the T cell response to gluten generates similar TCRs in all patients with a particular HLA type.
These TCRs are selected from the repertoire generated during T cell development in the thymus, whereby the elements involved in antigen recognition are edited from that encoded by the germline (inherited) to generate a huge and diverse array of binding elements that can recognise the limitless number of microbial antigens.
Hence, certain amino acid sequences are selected that recognise particular gluten peptides for a given HLA, but more significantly, certain sequences are shared between TCRs that recognise very different gluten peptides and very different HLA molecules.
The most recent work from this laboratory, published last month in Structure, cements these findings. What has been shown is that a genetically encoded residue on the T cell receptor can substitute for that of a functionally similar residue in the TCR that has been produced through genetic editing during T cell development.
Thus, that despite diverse TCR usage, gluten peptide sequence variability, and very different HLA usage, pathogenic T cells in coeliac disease bear TCRs that use convergent structural elements for recognition of the gluten peptides bound to the HLA molecules.
This provides a framework or launching pad to design drugs that interfere with the recognition of gluten by T cells. That a common mechanism of gluten recognition converges in a genetically, highly diverse population of patients is quite astonishing and provides an excellent avenue to disrupt the interaction across the spectrum. Small molecule oral drugs or monoclonal antibodies may be developed as inhibitors of the interaction thereby short-circuiting the inflammatory response generated by T cells in coeliac patients.
ARC Centre of Excellence in Advanced Molecular Imaging
The $39 million ARC-funded Imaging CoE develops and uses innovative imaging technologies to visualise the molecular interactions that underpin the immune system. Featuring an internationally renowned team of lead scientists across five major Australian Universities and academic and commercial partners globally, the Centre uses a truly multi scale and programmatic approach to imaging to deliver maximum impact.
The Imaging CoE is headquartered at Monash University with four collaborating organisations – La Trobe University, the University of Melbourne, University of New South Wales and the University of Queensland.