New insights into the way gluten causes damage in celiac disease revealed in Beyond Celiac funded research

Findings could pave the way for innovative treatments

By Amy Ratner, director of scientific affairs

Results of research funded by Beyond Celiac point to a more precise way that gluten sets off damage to the intestine in those who have celiac disease and could help in the development of innovative approaches to finding a treatment.

The study, by Arnold Han, MD, a gastroenterologist at Columbia University and recipient of the Beyond Celiac/Society for the Study of Celiac Disease Early Career Investigator grant, describes the way gluten triggers two kinds of T-cells to coordinate and cause damage.

New clues

T-cells are white blood cells that function as the body’s disease fighting soldiers and are part of coordinated immune system battle. In the case of celiac disease, these soldiers incorrectly read gluten peptides as the enemy, rally the immune response troops and go on the attack, with resulting destruction of the absorbing lining of the intestine.

 The new study, published in the journal Science Immunology, provides important clues about the way CD4 T-cell responses to gluten ultimately lead to intestinal damage by intraepithelial lymphocytes. Intraepithelial lymphocytes are T-cells found in the intestinal tract.

“We show that gluten somehow induces rapid and deliberate activation of the [intraepithelial lymphocytes],” Han said.

This was somewhat unexpected because the intraepithelial lymphocytes are not thought to recognize gluten on their own, he noted. The study suggests that these cells shift from anti-inflammatory defenders to pro-inflammatory attackers, leading to intestinal damage.

Role in developing new approaches to treatment

Evidence from the study, which is ongoing, could be used in the development of new treatments for celiac disease based on what it reveals about the way that gluten causes the immune reaction in celiac disease.

“An improved understanding of any disease process can inform new avenues for therapy,” Han said. Many celiac disease drugs currently being developed focus on the activation of the CD4 T-cells, but this new research with its improved understanding of how the intraepithelial cells are activated could contribute to treatments that target them, he noted.

Han and colleagues at Columbia University analyzed T-cells from the intestinal biopsies of 37 study participants in three categories — 11 with who had just been diagnosed and were considered to have untreated celiac disease, 19 with active celiac disease on a gluten-free diet and seven with potential celiac disease who had positive blood tests for celiac disease antibodies by no damage to the intestine. The study also included 17 participants who did not have celiac disease.

How study was done

Study participants in all three categories of celiac disease had an enriched number of intestinal T-cells, including CD4 helper cells, regulatory T-cells and CD8 intraepithelial cells.

Blood samples from study participants who had been on a strict gluten-free diet for at least six months and volunteered to eat four slices of gluten-containing white bread per day for three days, a gluten challenge, were also analyzed.

In celiac disease, although intestinal damage can heal completely on a gluten-free diet, changes in the intraepithelial cell population can persist for years, Han said. These persistent cells have distinct T-cell receptors and researchers are working to understand what the receptors are recognizing if it is not gluten. The receptors on the surface of T-cells play a significant role in immune response by activating the cells to respond to antigens, acting as a kind of warning system alarm switch. An antigen is a marker that tells your immune system whether something in your body is harmful or not.

Investigating antigens

In celiac disease, gluten is the antigen recognized by CD4 T-cells. “However, we don’t know the antigens for these intraepithelial cells that appear to cause damage,” Han noted. Previous research done by Han suggested that microbial antigens, which are microorganisms including bacteria, viruses and more, or self-antigens, which are normal substances found in a person’s body, are potentially being recognized by the intraepithelial lymphocytes.

The new study found that groups of cells that shared the same T-cell receptors, called T-cell clones, which were present in the intestinal biopsies of study participants with celiac disease were later seen in the blood following the gluten challenge. Researchers were able to track how a given T-cell clone behaved and found that the T-cells in the intestine were changing to become more inflammatory in the blood, Han said.

In ongoing research Han and colleagues are aiming to better understand how intraepithelial cells are activated by gluten. His research will also include study of celiac disease using organoids, tiny three-dimensional mini organs grown in a petri dish from the intestinal cells of celiac disease patients.

You can read the study here.