Researchers at the Mucosal Immunology and Biology Research Center at MassGeneral Hospital for Children (MGHfC) have discovered novel genes and pathways related to early stages in the development of celiac disease and the ongoing inflammation and comorbidities associated with the condition. The findings, published in PLOS One, include analyses of RNA sequences in duodenal biopsies from individuals with and without celiac  disease and are consistent with many previously described pathways in the development of celiac disease.

In collaboration with Regeneron Pharmaceuticals, Inc. – a biopharmaceutical company based in Tarrytown, New York – researchers performed whole-transcriptome shotgun sequencing of 12 patients with active celiac disease, 15 celiac patients in remission with no intestinal damage, and 15 individuals without celiac disease. By analyzing participants’ transcriptome – the total sum of transcribed RNA sequences – researchers discovered which genes were expressed and which genes were not expressed to determine genetic signatures linked to celiac disease.  

“We know that celiac disease is a multifactorial disease with about 57 genes associated with this autoimmune condition. 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,” says Maureen Leonard, MD, MMSc, clinical director of the Center for Celiac Research and Treatment at MGHfC, an instructor in Pediatrics at Harvard Medical School and first author of the study.

The results showed clear differences in gene expressions among the three groups. Researchers found significant differences in the expression of 945 genes between people with active celiac disease and non-celiac controls; 290 genes between people with celiac disease in remission and the non-celiac group; and 538 genes between the active celiac group and the celiac disease in remission group.

“The identified genes activated three major pathways: innate immunity, gut permeability and differentiation in cell maturation,” says Alessio Fasano, MD, director of the Center for Celiac Research and Treatment at MGHfC, a professor of Pediatrics at Harvard Medical School and senior author of the PLOS One report. “We can confirm that these functions are instrumental when you develop celiac disease.” Expression of some of the genes returned to normal when patients were placed on a gluten-free diet, he notes, and some did not. Fasano notes that this finding could provide some insight into why some people have persistent intestinal damage even after following a strict gluten-free diet.

From the enormous array of data generated, researchers chose to focus on functional pathways that were significantly different between the active celiac group and those in remission. Two of the three top perturbed pathways in the active celiac group involved signaling by cytokines and chemokines, which are known as the immune system’s “first responders” and markers of inflammation in innate immunity in the early stages of disease development. The researchers also found evidence to suggest that the risk of co-morbid autoimmune disorder may be high in active celiac disease, as pathways for type 1 diabetes, lupus and autoimmune thyroid disease also were upregulated.

Identifying potential targets for therapeutic intervention in celiac disease and other autoimmune conditions is a long-term goal of the research group. “This study is only the beginning. Our findings provide the framework for future validation studies to investigate the early steps in celiac disease pathogenesis and to examine the remission state,” says Leonard. Research is underway at other centers for the use of the transcriptome in targeted therapy in Inflammatory Bowel Disease, and Leonard and Fasano hope to see this replicated for celiac disease.

Additional co-authors of the paper are Yu Bai, PhD; Matthew Sleeman, PhD; and Cagan Gurer, PhD, of Regeneron Pharmaceuticals, Inc.; Maria R. Fiorentino, PhD; Gloria Serena, PhD; Kourtney Nickerson, PhD; Craig Sturgeon, PhD; and Stephanie Camhi, of the MGHfC Center for Celiac Research and Treatment Center and the MGHfC Mucosal Immunology and Biology Research Center; Aubrey Katz, MD, of MGHfC’s Division of Pediatric Gastroenterology and Nutrition; and Barbara Nath, MD, and James Richter, MD, of the Massachusetts General Hospital Department of Gastroenterology. This work was supported partially by National Institutes of Health grants DK 048373 and DK 104344 and by Regeneron Pharmaceuticals, Inc.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of “America's Best Hospitals.”