RNA study holds clues to why celiac disease develops

April 24, 2019

Study also provides insight into why some people have persistent intestinal damage on the gluten-free diet

By Amy Ratner, Medical and Science News Analyst

The reasons some people develop celiac disease in the first place and why some have persistent intestinal damage even when on the gluten-free diet may be found in novel genes discovered by researchers at MassGeneral Hospital for Children.

In a study published in the journal PLOS One, scientists from the Center for Celiac Research and Treatment and colleagues performed RNA sequencing on intestinal biopsies from those with active celiac disease, celiac disease considered to be in remission and controls who did not have celiac disease.

Active celiac disease was defined as having significant destruction of the villi, the absorbing fingerlike projections in the intestine. Study participants with inactive celiac disease were required to have been on the gluten-free diet for at least one year and have relatively normal villi.

Participants in all three groups had the HLA DQ2 or DQ8 genes that are found in 98 percent of those who develop celiac disease, but the study found clear differences in other genes when comparing the three study groups.

Ribonucleic acid (RNA): an important biological macromolecule that functions to convert the genetic information encoded by DNA into proteins.

The study found “a unique signature of genes related to innate immunity” exclusively in those with celiac disease irrespective of disease status.” This finding confirms the important role of the innate immune system in celiac disease, the study says.

Innate immune system: the first part of the body to detect invaders and activate cells to attack and destroy while also informing and modulating the adaptive immune response that follows this first line of defense. In celiac disease, gluten from wheat, barley and rye is mistakenly identified as an invader. 


Additionally, the study found increased activity of novel genes involved in the immune response machinery and cell adhesion process in the intestinal lining of those with active celiac disease compared to those with inactive celiac disease.

“Together our findings support a possible link between the microbiome, innate immune response and the development of celiac disease and highlight the possible associations that with future validations may lead to crucial knowledge of the steps leading to the loss of tolerance to gluten,” the authors wrote.

The study analyzed the total sum of transcribed RNA sequences and discovered which genes were expressed and which were not to determine genetic signatures linked to celiac disease.

Differences in genes

Scientists found 945 differences in genes when comparing those with active celiac disease to those without the condition; 538 between those with active celiac disease and those whose celiac disease was inactive and 290 genes between those with celiac disease that was inactive compared to the controls.

“We know that celiac disease is a multifactorial disease with about 57 genes associated with this autoimmune condition,” said Maureen Leonard, MD, clinical director of celiac center. “By performing RNA sequencing, we have uncovered additional genetic signatures and moved closer to identifying targets for future therapeutic agents in celiac disease and possibly other autoimmune conditions.”

The identified genes activated three major pathways – innate immunity, gut permeability and differentiation in cell maturation, according to Alessio Fasano, MD, director of the celiac center and the senior author of the study. “We can confirm these functions are instrumental when you develop celiac disease,” he said. Some of the genes returned to normal when a patient with celiac disease went on a gluten-free diet, while others did not. This could provide insight into why some people have persistent intestinal damage even when they follow a strict gluten-free diet, he added.

The study focused on differences between those with active and inactive celiac disease. In those with active celiac disease, two of the three top disrupted pathways involved cytokines and chemokines, the immune system’s “first responders” and markers of inflammation in innate immunity in the early stages of disease development, the study found.

Cytokines: small secreted proteins released by cells that have a specific effect on the interactions and communications between cells. There are both pro-inflammatory and anti-inflammatory cytokines. Chemokines: a family of small cytokines or signaling proteins secreted by cells.


In active celiac disease, a higher risk of other autoimmune conditions, such as type 1 diabetes, lupus and autoimmune thyroid disease was also noted.

“This study is only the beginning,” Leonard said. “Our findings provide the framework for future validation studies to investigate the early steps in celiac disease pathogenesis and the examine the remission state.”

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