Eosinophilic Gastrointestinal Diseases

As a physician-scientist, my long-term objective is to define immunologic mechanisms of gastrointestinal inflammation that drive clinical phenotype/outcome. This is key to identifying novel therapeutic targets, improving outcomes, reducing morbidity and personalizing care. My focus is on Eosinophilic Gastrointestinal Diseases (EGID), in particular Eosinophilic Esophagitis (EoE), Eosinophilic Gastritis (EG), and Eosinophilic Gastroenteritis (EGE). EoE, in particular, involves symptoms of esophageal dysfunction and eosinophil-predominant inflammation isolated to the esophagus secondary to chronic exposure to one or more dietary antigens. Left untreated, the long-term complication of the diseases is due to fibrostenosis. In addition to eosinophilia, most patients have mucosal mastocytosis. Mast cells are tissue resident immune cells, well-described as a component of the chronic inflammation seen in both disease. Packed with histamine granules, mast cells can be triggered by luminal contents to release histamine through degranulation. Histamine, a pro-inflammatory small molecule derived from histidine, acts through 4 receptors (H1R-H4R), of which the gut expresses all but H3R. Notably, H4R expression is restricted to the immune system. In addition, mast cells release several proteases, which are also stored in granules, along with de novo synthesized leukotrienes, cytokines, and chemokines. My laboratory studies the role of mast cell activation, histamine and its receptors, and the granule-associated proteases in driving clinical, endoscopic and histologic changes in EGIDs. In addition, my laboratory studies the role of mast cells activation in Ulcerative Colitis (UC), a subtype of inflammatory bowel disease (IBD) characterized by blood diarrhea, and T-helper lymphocyte type 2 inflammation restricted to the colonic mucosa. Recently, we identified a role for mucosal mast cell derived histamine and the histamine 4-receptor (H4R) in recruiting neutrophils to the colon. We are actively working to identify the cellular target expressing H4R and its role. In the laboratory, animal models of these diseases are utilized to characterize the requirements and consequences of mast cells and their mediators to define mechanism. We are actively studying the interaction between mast cells and the epithelium and build 3-D Air liquid interface models of the esophagus to better define this. With the knowledge gained from these models, patient biopsies are interrogated by RNA (single cell and bulk) and protein analysis to corroborate the findings, further an understanding of the disease process, and support the need for new therapeutic options.