A research team led by Mount Sinai has uncovered mechanisms of abnormal immune cell function that may lead to Crohn's disease, according to findings published in Science Immunology on March 21. The researchers said their discovery provides better understanding of disease development and could inform the development and design of new therapies to prevent inflammation before it starts in the chronic disorder.
Crohn's disease is an inflammatory bowel disease (IBD) that causes chronic inflammation of the gastrointestinal (GI) tract, and symptoms can include abdominal pain, diarrhea, weight loss, anemia, and fatigue. Inflammation is the body's natural response to infection or injury, but prolonged and untreated inflammation may cause damage to healthy cells, tissues, and organs. White blood cells in the GI tract known as intraepithelial lymphocytes express the gamma delta T cell receptor (gamma delta IELs), which prevent infection and provide surveillance for the intestinal barrier. These gamma delta IELs are often reduced in patients with active Crohn's disease.
The researchers said their study is the first to show that gamma delta IELs are critical to maintain a balance between pro-inflammatory and regulatory immune responses, and these cells are impaired during the onset and progression of long-term inflammation in the lower small intestine.
"Previous studies assessing patient biopsies revealed a decrease in gamma delta IELs in those with active IBD. However, it was unknown whether the loss of these cells was a cause or consequence of disease," said corresponding author Karen Edelblum, PhD, Associate Professor of Pathology, Molecular and Cell-Based Medicine at the Icahn School of Medicine at Mount Sinai. "Our findings now show that gamma delta IELs are substantially decreased weeks before clinical or histological evidence of disease in a mouse model of Crohn's disease-like ileitis. Furthermore, we were able to generate a timeline of events leading to the dysregulation of gamma delta IELs that mirrored findings from prior studies in patients with IBD."
The researchers used a mice model of Crohn's disease-like inflammation in the lower small intestine to analyze human disease. Before tissue damage began, they found that pro-inflammatory proteins impaired the communication between gamma delta IELs and neighboring intestinal epithelial cells. As a result, the majority of these gamma delta IELs failed to survive, and barrier surveillance was significantly compromised. The research team also identified that gamma delta IELs lost their ability to suppress other pro-inflammatory IELs responsible for tissue damage, indicating that the early loss of regulatory gamma delta IELs may contribute to the activation of inflammation in Crohn's disease.
The researchers said loss of gamma delta IELs could be used as a predictive biomarker for disease relapse or patient responsiveness to treatment. Additionally, development of future therapies that boost the function of gamma delta IELs may provide a new way to maintain remission in IBD patients or prevent disease development in susceptible individuals.
Researchers from Rutgers University, Case Western Reserve University, and Children's Hospital of Los Angeles contributed to this study. The study was supported by grants from the National Institutes of Health, the Crohn's and Colitis Foundation, A*STAR, and the New Jersey Commission on Cancer Research.
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Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients' medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 11 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek's® "The World's Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals" and by U.S. News & World Report's® "Best Hospitals" and "Best Children's Hospitals." The Mount Sinai Hospital is on the U.S. News & World Report® "Best Hospitals" Honor Roll for 2024-2025.
