10.11.2024
Gluten intolerance
The cause of gluten intolerance has finally been identified. A promising treatment for the condition
A new study shows that the epithelial cells that line the cells lining the inside of the intestine play a key role in the immune response in gluten intolerance (or celiac disease). Until now, it was thought that only immune cells were involved in this response. Epithelial cells also trigger a stronger signal when the response to gluten is accompanied by the presence of pathogens. Celiac disease is characterized by a marked intolerance to any food containing gluten (made from wheat, rye or barley). It manifests as severe intestinal pain, abdominal bloating, diarrhea, and sometimes even gastric reflux or vomiting. These symptoms interfere with nutrient absorption and in the long run can lead to other serious health problems such as osteoporosis, infertility, and various digestive cancers. Although originally thought to be a food hypersensitivity disorder, it is now considered more of an autoimmune disease because of its similarities to tissue-specific diseases (such as type 1 diabetes and rheumatoid arthritis). These diseases are typically associated with the human major histocompatibility complex (HLA), which facilitates antigen recognition by T lymphocytes. In addition, about 90% of patients diagnosed with celiac disease carry genes encoding the HLA-DQ2.5 protein, and the remaining 10% carry the gene encoding HLA-DQ8.
However, the mechanisms underlying these associations are unclear, as people who express HLA genes do not necessarily develop gluten intolerance, but instead may suffer from other autoimmune diseases. On the other hand, the disease is characterized by lesions in the epithelial tissue of the intestinal wall.
However, it is not known exactly how these lesions are involved in the immune responses that characterize the disease. This lack of understanding has severely hampered the development of treatments. As a result, "the only treatment for celiac disease to date has been to completely eliminate gluten from the diet," explains new study co-author Elena Verdu of the Farncombe Family Digestive Health Research Institute in a McMaster University (in Hamilton, Canada) press release. However, "this is difficult to achieve and experts agree that a gluten-free diet is not enough," she adds. To explore potential avenues for the development of new treatments, Verdu and her colleagues further investigated the involvement of intestinal epithelial cells in the immune response to gluten. The results of the study are detailed in the journal Gastroenterology. Enhanced immune response in the presence of pathogens The team of authors of the new study examined the interactions between epithelial cells, gluten and T lymphocytes in monolayers of organoids expressing HLA-DQ2.5. In particular, this allows the analysis of different molecular interactions at the level of epithelial cells in isolation, which would not be possible in vivo due to the complexity of the natural intestinal environment.
To create the organoids, they cultured mouse epithelial cells genetically modified to express the HLA-DQ2.5 protein. Immune responses were analyzed by exposing them to inflammatory cytokines and pre-digested or undigested gluten. "This allowed us to determine cause and effect and prove exactly if and how a response occurs," explains Tohid Didar of McMaster University's School of Biomedical Engineering, corresponding author of the study. The researchers found that epithelial cells, although not categorized as immune cells, play an important role in activating the immune response in celiac disease, particularly in T-cell proliferation and secretion of inflammatory cytokines. Surprisingly, gluten metabolized by Pseudomonas aeruginosa (an opportunistic bacterium that can cause various types of infections) increased T-cell proliferation and activation. The experts concluded that immune activation of epithelial cells increases in the presence of pathogens. This means that it is possible to detect a pathogen in a person at risk of developing the disease and suppress its interaction with gluten and the intestinal epithelium to prevent the disease.
According to experts, these results suggest that epithelial cells may be promising targets for the treatment of the disease. For example, both adaptive immunity (involving T and B lymphocytes) and innate immunity (which does not require antigen presentation and involves macrophages and neutrophils) could be modulated in patients with the disease. "Accurately identifying the 'spark' of the immune response may stimulate drug discovery studies to inhibit this newly understood role of the epithelium, using drugs already in clinical trials," concludes Verdu.