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A team of researchers from Mount Sinai has identified key mechanisms behind the dysfunctional immune responses associated with Crohn’s disease, revealing insights that could significantly aid in the prevention and treatment of this condition. Their findings were detailed in the journal Science Immunology on March 21.
Crohn’s disease, classified as one of the inflammatory bowel diseases (IBD), results in persistent inflammation of the gastrointestinal (GI) tract. Common symptoms include abdominal discomfort, diarrhea, weight fluctuations, anemia, and fatigue. While inflammation serves as a protective response to infection or injury, prolonged inflammation can inflict damage on healthy cells and tissues. Within the GI tract, a subset of white blood cells known as intraepithelial lymphocytes (IELs)—specifically the gamma delta T cell receptor-expressing IELs (gamma delta IELs)—play a crucial role in infection defense and maintaining the integrity of the intestinal barrier. Notably, the presence of gamma delta IELs is often diminished in individuals suffering from active Crohn’s disease.
The research is groundbreaking, marking the first instance of demonstrating the pivotal role of gamma delta IELs in balancing pro-inflammatory and regulatory immune responses. Findings indicate that these immune cells become impaired during the initial stages and progression of chronic inflammation, particularly in the lower small intestine.
“While past research on biopsy samples from patients indicated a reduction in gamma delta IELs among those with active IBD, the relationship between the loss of these cells and the disease was unclear,” explained Karen Edelblum, PhD, Associate Professor of Pathology, Molecular and Cell-Based Medicine at the Icahn School of Medicine at Mount Sinai. “Our study reveals that gamma delta IELs show significant decline well before any clinical or microscopic signs of the disease are evident in a mouse model that mimics Crohn’s disease-like ileitis. Moreover, we were able to outline a timeline of events leading to the dysfunction of gamma delta IELs that aligns with previous research findings in IBD patients.”
To study Crohn’s disease, the team utilized a murine model that reflects inflammation patterns seen in humans. They discovered that prior to any observable tissue damage, pro-inflammatory proteins disrupt communication between gamma delta IELs and adjacent intestinal epithelial cells. Consequently, the majority of gamma delta IELs fail to survive, which significantly undermines the intestinal barrier’s ability to surveil for potential threats. In addition, the team found that these cells lost their capability to regulate other pro-inflammatory IELs that contribute to tissue harm, suggesting that the initial depletion of gamma delta IELs could trigger inflammatory processes in Crohn’s disease.
The researchers propose that monitoring the levels of gamma delta IELs could be instrumental as a predictive biomarker for anticipating disease relapses or gauging patient responses to treatments. Furthermore, future therapeutic strategies aimed at enhancing the functional capacity of gamma delta IELs could represent a novel approach to sustaining remission in patients with IBD or preventing disease onset in individuals at risk.
This study also involved collaboration with researchers from Rutgers University, Case Western Reserve University, and Children’s Hospital of Los Angeles. Financial support came 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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