How and when does the reaction to gluten begin in coeliac disease? A new Canadian study offers potential answers

Diet remains the only treatment option for now

Coeliac disease affects approximately 1% of the population. It occurs in genetically predisposed individuals and is triggered by the ingestion of gluten. To date, there is no available treatment, leaving patients with the disease no choice but to completely eliminate gluten from their diets. Even trace amounts of gluten can cause intestinal pain, impair nutrient absorption, and increase the risk of severe long-term complications.

Exploring interactions

Immune cells play a central role in the inflammatory response to gluten. In coeliac disease, the main histocompatibility complex class II (MHC II) is critical. Ninety-five percent of patients with this disease are positive for HLA-DQ2, and the remaining 5% are positive for HLA-DQ8. The activity of these molecules activates helper T lymphocytes (TH), which express the CD4+ protein on their surface (CD4+ T lymphocytes). These cells then initiate the synthesis of pro-inflammatory cytokines, leading to an inflammatory process that damages enterocytes.

A team of researchers from McMaster University in Hamilton, Canada, recently discovered that the intestinal epithelium also plays an active role in the inflammatory response to gluten and that it helps activate the immune response, particularly T cells. The specific genes encoding MHC II are not sufficient alone for the development of coeliac disease. The study therefore focused on interactions between IECs, gluten, and T lymphocytes.

Organoid model

To investigate this, the researchers developed an organoid model expressing human HLA-DQ2.5, which is present in 90% of patients with coeliac disease. HLA proteins are antigen-presenting cells (APCs) that enable lymphocytes to recognise antigens, in this case, gluten. IECs were freshly isolated from human intestinal tissue samples or from the duodenum and proximal jejunum of mice.

Human samples were obtained via biopsy during endoscopy from several patients with either active or treated coeliac disease who did not have concurrent autoimmune or chronic inflammatory disorders. The animal study population included various transgenic groups of mice expressing only human, not murine, MHC II molecules. Organoid monolayers were derived from these mouse models. The team observed how immune cells were activated in the presence of gluten.

Expression of epithelial MHC II

In patients with active coeliac disease and gluten-immunised DR3-DQ2.5 mice, epithelial MHC II expression was demonstrated. MHC II expression was also observed in organoid-derived monolayers from gluten-immunised DR3-DQ2.5 mice. In T-cell cultures, gluten increased the proliferation of CD4+ T lymphocytes, expression of T lymphocyte activation markers, and the release of interleukins IL-2, IL-15, and interferon-gamma (IFN-γ).

In human samples, MHC II expression was more commonly observed in intestinal epithelial cells from patients with active coeliac disease compared to those with treated coeliac disease who achieved a Marsh score of ≤ 1.

Overall, the findings revealed that in coeliac disease, the intestinal epithelium contributes to modulating the CD4+ T-cell response, exhibiting characteristics of APCs. Furthermore, the proliferation and activation of CD4+ T lymphocytes were more pronounced when gluten was metabolised by the bacterium Pseudomonas aeruginosa. This suggests that the epithelium sends stronger signals to immune cells in the presence of pathogens.

Hope for therapeutic development

The study authors suggest that their findings could be instrumental in coeliac disease therapy. They concluded that gluten antigens are effectively presented by intestinal epithelial cells expressing MHC II, leading to the activation of specific CD4+ T cells. They also proposed that it might be possible to detect pathogens in individuals at risk of coeliac disease and preventively inhibit their interactions with gluten and the intestinal epithelium. Moreover, they noted that therapies targeting IECs could offer a novel approach for patients with coeliac disease to modulate both adaptive and innate immunity.

Editorial Team, Medscope.pro

Source:

Rahmani S., Galipeau H. J., Clarizio A. V. et al. Gluten-dependent activation of CD4+ T cells by MHC class II-expressing epithelium. Gastroenterology 2024 Nov; 167 (6): 1113–1128, doi: 10.1053/j.gastro.2024.07.008.