Eosinophilic Esophagitis - Pathophysiology and its Clinical Implications

Eosinophilic Esophagitis is an antigen mediated chronic disease that is distinct from gastroesophageal reflux disease. EoE an emerging clinical problem that is rapidly growing in incidence and in recognition. It is characterized clinically by feeding dysfunction, dysphagia and reflux-like symptoms. Histologically EoE is identifiable by a dense epithelial eosinophilic infiltrate. Experimental modeling and clinical studies over the last decade have greatly improved our understanding of this disease and led to improvements in clinical understanding and the assessment of therapeutic options for patients and their clinicians who manage this disease. In this review we review the cliniopathologic diagnostic criteria and our understanding of EoE as an allergic disease with genetic and immunological components in the pathophysiology. We make note of the berth of studies defining the importance of the epithelial barrier and discuss the concept of barrier function as an initiating or perpetuating factor for this disease. The relationship between the symptoms of dysphagia, feeding dysfunction and our current knowledge of the underlying pathophysiologic mechanisms of these clinical indicators, as well as advances in clinical assessment of decreased esophageal distensibility and narrowing in EoE patients. Lastly, therapeutic implications relating to the advances that have led to our current understanding of the pathophysiology of EoE are explored

Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases

Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body as well as controlling the absorption of nutrients, fluid and solutes (1, 2). A series of protein complexes including the adherens junction, desmosomes, and tight junctions (TJ) function as the principal barrier in paracellular diffusion (3) as well as regulators of intracellular solute, protein and lipid transport (4). TJs are composed of a series of proteins called occludins, junctional adhesion molecules (JAM), and claudins (5, 6) that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases

Involvement of PU.1 in Mast Cell/Basophil-Specific Function of the Human IL1RL1/ST2 Promoter

Background: The human IL1RL1/ST2 gene encodes IL33 receptor. Recently, IL33 has been recognized as a key molecule for the development of Th2 response. Although mast cells and basophils are major targets of IL33 and play important roles in IL33-mediated Th2-type immune responses, the expression mechanism of ST2 in mast cells and basophils is largely unknown. In the present study, we analyzed regulation mechanism of the human ST2 promoter in the human mast cell line LAD2 and basophilic cell line KU812. Methods: Promoter activity was determined by reporter assay with plasmids carrying the wild-type ST2 promoter obtained from human genomic DNA and its mutant. The transcription factor binding to the identified cis-element was identified by an electrophoretic mobility shift assay (EMSA). The effect of candidate transcription factor on ST2 expression was confirmed by analyzing ST2 mRNA level in siRNA-introduced cells. Results: Reporter assay demonstrated that a cis-element of typical Ets-family binding sequence was critical for promoter activity in LAD2 and KU812. An Ets-family transcription factor PU.1 bound to this element in an EMSA. When PU.1 expression was suppressed by siRNA, sT2 mRNA level was significantly reduced in KU812. Conclusions: These observations indicated that PU.1 positively regulates the ST2 promoter as a transcription factor that directly transactivates the ST2 promoter via Ets-family-related cis-element in mast cells and basophils