LAUSR

Celiac disease (CD), the most common chronic autoimmune enteropathy present in Western populations, is triggered by gluten ingestion in genetically susceptible individuals carrying the HLA DQ2 and/or DQ8 loci [1]. Gluten, a high molecular weight protein present in the endosperm of grass-related grains, including wheat, barley, and rye, is stored within seeds in order to ensure a stable nutrient supply supporting the germination and development of young plants. Gluten-containing cereals, the most important crop in the world, are used to make food products such as pasta, bread, other baked and pastry products. The viscoelastic and stabilizing properties of gluten have fostered its use as an additive in the baking industry; furthermore, it gives food greater palatability due to the creation of disulfide bonds that in combination with atmospheric oxygen and nitrogen alter the properties of the dough as a function of the sulfhydryl and disulfide content [1]. Gluten is a composite of two classes of protein, glutenins and prolamins (gliadin, secalin, and hordein), which can be further fractionated to produce peptides. Pepsin– trypsin-resistant gliadin (PT-G) is an undigested gliadin fragment that substantially contributes to the pathogenesis of CD by altering intercellular tight junctions (TJs) [2]. In CD, a genetic predisposition and exposure to environmental triggers cooperate in the loss of the intestinal barrier function. Gluten peptides and gliadins permeabilize the gut, which provokes an immunomodulatory cytotoxic effect and opens TJs. Subsequently, the deregulated traffic of macromolecules, due to the ‘‘leaky gut,’’ severely damages the intestine, thus fueling the chronic inflammatory process. The TJ, a dynamic protein complex, is the primary determinant of the paracellular flux of fluid and solutes in a healthy epithelium. The integrity of the barrier is important for the separation of the two compartments: the luminal and the submucosal sides [3]. TJs govern the permeability of the intestinal mucosal barrier; even minimal alterations in TJ function allow the passage of potentially toxic macromolecules through the intercellular spaces in the subcellular matrix, a condition called ‘‘leaky gut syndrome’’ that is common in many inflammatory diseases of the small bowel [4–6]. The three-dimensional structure of many cells is governed by a network of polymeric proteins including actin filaments termed the cytoskeleton, the organization of which is implicated in the pathogenesis of CD. Gliadin causes the disarrangement and disappearance of epithelial cellular organization in CD patients [7]. TJs are demonstrably associated with the actin filaments in epithelial cells assembling in a fusion structure called ‘‘kissing points.’’ The inflammation and autoimmunity that occurs secondary to the ingestion of gluten in predisposed subjects disconnects innate and adaptive immunity. Zonulin is the only known modulator of intercellular TJs, regulating intestinal permeability [8]. During the acute phase of CD, the zonulin pathway is upregulated. For all the aforementioned reasons, investigation is extremely active into drugs & Luca Elli [email protected]