by Foods containing even tiny amounts of gluten can cause severe pain for about one in a hundred people.
Although a domino effect of immunological reactions can be traced back to its genetic roots, numerous other factors also play a role. This makes it difficult to trace the exact chain of events that leads to the development of gluten intolerance.
An international team led by scientists from McMasters University in Canada has used genetically modified mice to discover the crucial role of the cells that make up the intestinal mucosa, an important milestone that could lead to new therapies.
Celiac disease is essentially an autoimmune disease triggered by the presence of a group of structural proteins known as gluten in the intestine.
Eating virtually any food made from wheat, barley or rye – most baked goods, breads and pasta – puts people at risk of bloating, pain, diarrhea, constipation and sometimes reflux and vomiting.
Currently, the only way to avoid symptoms is to avoid the foods that trigger them.
“Today, we can only treat celiac disease by completely eliminating gluten from the diet,” says Elena Verdu, a gastroenterologist at McMasters University. “It’s difficult, and experts agree that a gluten-free diet is not enough.”
About 90 percent of people diagnosed with the disease carry a pair of genes that encode a protein called HLA-DQ2.5. Of the remaining 10 percent, most have a similar protein called HLA-DQ8.
Like other types of “HLA” (human leukocyte antigen) proteins, these proteins hold up parts of fallen invaders like macabre trophies on a class of immune cells, thus warning other defensive tissues to be on guard.
In the specific case of HLA-DQ2.5 and HLA-DQ8, the proteins are shaped to hold onto chunks of gluten peptides that resist digestion and instruct murderous T cells to go hunting.
Unfortunately, these instructions are not particularly clear when it comes to distinguishing between a threat and similar-looking materials in our bodies. This means that people with the corresponding genes are at risk for a number of autoimmune diseases.
However, not everyone who expresses HLA-DQ2.5 or HLA-DQ8 develops an immune disorder such as celiac disease. For this to happen, the torn pieces of gluten must first be transported through the intestinal wall by a transport enzyme that binds to the peptide and changes it so that it is even more recognizable.
Cells in the intestinal wall are responsible for releasing this transport enzyme into the intestine, so they clearly play a crucial role in the early stages of the disease. They are also known to express the family of proteins that include HLA-DQ2.5 and HLA-DQ8, which are typically regulated by inflammatory responses in the intestine.
It is unclear how this starting point actually works for people with celiac disease within the disease itself.
To focus on this important link in the chain, the research team examined the expression of the key immune complex in the cells of the intestinal mucosa of people with treated and untreated celiac disease, as well as in mice with the human genes for HLA-DQ2.5.
They then created functional living models of the intestine, called organoids, from the mice’s intestinal cells to study the expression of their immune proteins up close by exposing them to pro-inflammatory influences and pre-digested and intact gluten.
“This allowed us to narrow down the specific cause and effect and demonstrate exactly whether and how the reaction occurs,” says Tohid Didar, a biomedical engineer at McMasters University.
This made it clear that the cells of the intestinal mucosa were not just passive spectators, suffering collateral damage in the misguided attempt to rid the body of gluten, but that they were the main actors, representing a mixture of gluten fragments that were broken down by intestinal bacteria and transported enzymes directly to gluten-specific immune cells.
By understanding the types of tissues affected and how they are exacerbated by the presence of pro-inflammatory microbes, researchers can identify new targets for future treatments and potentially enable millions of people around the world to enjoy the odd gluten-containing pastry without the risk of discomfort.
This research was published in Gastroenterology.
