Celiac disease is an autoimmune disorder, with no available treatment, that affects roughly one percent of the population. People with celiac disease must maintain a strict gluten-free diet. Consumption of even trace amounts of gluten can trigger painful symptoms in the gut, impede the absorption of nutrients, and raise the risk of other serious long-term issues.
“The only way we can treat celiac disease today is by fully eliminating gluten from the diet. This is difficult to do, and experts agree that a gluten-free diet is insufficient,” says Elena Verdu, MD, PhD, a professor of gastroenterology and director of McMaster’s Farncombe Family Digestive Health Research Institute.
Now, a team of researchers centered at McMaster University in Canada has unlocked a significant piece of the puzzle in the understanding of the disease: how and where the gluten response begins. It had previously been thought that the inflammatory response to gluten exclusively involved immune cells. But the new findings suggest that the inner lining of the upper intestine—the epithelium which is composed of a variety of cells that are not classically part of the immune system—also plays an active role in directing the inflammatory response to gluten.
[Georgia Kirkos, McMaster University]
Damage of the intestinal epithelial cells (IEC) is a hallmark of celiac disease. However, how this damage activates the immune response, and specifically T cells, in a gluten dependent manner, is not understood. This study sought to investigate IEC-gluten-T-cell interactions. To do that, the researchers developed an organoid model expressing human major histocompatibility complex class II (HLA-DQ2.5) which facilitates gluten antigen recognition by CD4+ T cells in celiac disease.
“This allowed us to narrow down the specific cause and effect and prove exactly whether and how the reaction takes place,” says Tohid Didar, PhD, associate professor at McMaster’s School of Biomedical Engineering.
The team observed how immune cells are activated by the presence of gluten. More specifically, the findings showed that “patients with active celiac disease and gluten-immunized DR3-DQ2.5 mice demonstrated epithelial MHCII expression.” In addition, organoid monolayers derived from the gluten-immunized mice expressed MHCII and the MHCII was upregulated by IFN-γ. In organoid monolayer T-cell co-cultures, the authors write, “gluten increased the proliferation of CD4+ T cells, expression of T-cell activation markers, and the release of interleukin-2, IFN-γ, and interleukin-15 in co-culture supernatants.”
The team concludes that gluten antigens are “efficiently presented by MHCII-expressing IECs, resulting in the activation of gluten-specific CD4+ T cells.” This is enhanced by gluten predigestion with microbial elastase, meaning the epithelium sends stronger signals to immune cells if pathogens are also present. Given this result, it may be possible to detect pathogens in a person at risk of developing the disease, and inhibit the interactions with gluten and the gut epithelium to prevent the disease.
Determining the initiation of the immune response could stimulate research into drug delivery to inhibit this newly found role of the epithelium, Verdu says. In addition, the authors note that therapeutics directed at IECs may offer a novel approach for modulating both adaptive and innate immunity in celiac disease patients.
