Interestingly, a marked segment of the EE transcriptome is usually directly induced by IL-13 treatment of primary esophageal epithelial cells (including eotaxin-3 as the top gene induced by IL-13)

Interestingly, a marked segment of the EE transcriptome is usually directly induced by IL-13 treatment of primary esophageal epithelial cells (including eotaxin-3 as the top gene induced by IL-13).79 EE transcriptome genes regulated by IL-13 include periostin (markedly induced by IL-13 and overexpressed in EE)83 and filaggrin (markedly down-regulated by IL-13 and decreased in EE).12 Periostin is a fascilin domain name containing extracellular matrix molecule that regulates eosinophil adhesion and promotes eotaxin-induced eosinophil recruitment.83 Filaggrin is a skin structural barrier protein whose loss of function is associated with marked TNF-alpha increases in skin permeability and susceptibility to atopic dermatitis in humans84 and atopic sensitization in mice.85 Notably, in contrast to atopic dermatitis that is associated with loss of function genetic variants in the filaggrin gene, EE is associated with a functional impairment in filaggrin expression. relapse. As such, eosinophilic esophagitis is usually a disease with the unique features of chronic esophagitis, atopy, immune sensitization to oral antigens, reversibility and familial association. induces simultaneous eosinophilic airway and esophageal inflammation (without inducing lower gastrointestinal eosinophilia).73 Furthermore, intratracheal delivery of human or mouse IL-13 induces dose-dependent experimental EE;75 this process can be blocked with a therapeutic anti-human IL-13.76 Epicutaneous allergen sensitization potently primes for respiratory allergen-induced experimental EE.77 This latter finding may be particularly important for understanding EE because a large fraction of EE patients suffer from preceding allergic skin disease (atopic dermatitis).22 Collectively, these experimental systems demonstrate an intimate connection between development of eosinophilic inflammation in the respiratory tract and esophagus not only in response to external allergic triggers but also intrinsic Th2 cytokines, and they highlight the potential for sensitization to occur via cutaneous antigen exposure. It is notable that patients with allergic rhinitis have seasonal increases in esophageal eosinophils and patients with EE have seasonal variations in their symptoms,78 providing clinical evidence supporting a contributory role for aero-allergen-driven eosinophil-associated responses in the esophagus. Experimental modeling in mice has established that Th2 signaling is required for induction of experimental EE. In particular, mice with the targeted deletion of STAT6 are guarded (in part) from allergen- and IL-13-induced experimental EE.75, 77 Further, IL-13-deficient mice have impaired allergen-induced EE.77 Notably, IL-13 is overexpressed in the esophagus of EE patients and selectively induces the eosinophil activating and chemoattractant factor eotaxin-3 by a transcriptional mechanism in esophageal epithelial cells.79 There is marked overexpression of 1% of the human genome in the esophagus of EE patients compared with normal individuals and patients with CE.12 The EE transcriptome is highly conserved across patient phenotypes including gender, age and familial variants and includes eotaxin-3 as the most highly induced gene.12, 80, 81 Eotaxin-3 mRNA levels in esophageal biopsy tissue present in paraffin blocks can be used to distinguish EE and GERD.82 Comparison of allergic and non-allergic EE patients revealed that GSK J1 this gene GSK J1 transcript signature is markedly conserved across these two major patient phenotypes.12 This demonstrates that this effector phase of the disease is conserved between individuals despite the driving trigger of the inflammation. Interestingly, a marked segment of the EE transcriptome is usually directly induced by IL-13 treatment of primary esophageal epithelial cells (including eotaxin-3 as the top gene induced by IL-13).79 EE transcriptome genes regulated by IL-13 include periostin (markedly induced by IL-13 and overexpressed in EE)83 and filaggrin (markedly down-regulated by IL-13 and decreased in EE).12 Periostin is a fascilin domain name containing extracellular matrix molecule that regulates eosinophil adhesion and promotes eotaxin-induced eosinophil recruitment.83 Filaggrin is a skin structural barrier protein whose loss of function is associated with marked increases in skin permeability and susceptibility to atopic dermatitis in humans84 and atopic sensitization in mice.85 Notably, in contrast to atopic dermatitis that is associated with loss of function genetic variants in the filaggrin gene, EE is associated with a functional impairment in filaggrin expression. Notably, IL-13 down-regulates filaggrin gene expression in skin keratinocytes,86 providing a mechanism by which food antigen-elicited Th2 cell adaptive immunity may impair esophageal barrier function, perhaps propagating local inflammatory processes GSK J1 (including sensitivity to acid) and increased antigen uptake in the GSK J1 esophagus. These processes may be particularly important as there are elevated levels of activated mast cells, B cells and evidence for in situ production of immunoglobulins in the esophagus of EE patients, as demonstrated by histological analysis and transcriptome expression .12, 64, 66, 87 Support for a key role of T cells in the pathogenesis of EE is derived from analysis of lymphocyte deficient mice. T cell but not B cell deficient mice fail to develop antigen-induced EE.88 Notably, CD8 and CD4 cells are largely dispensable for the induction of em Aspergillus fumigatus /em -induced EE,88 highlighting the involvement of a unique component of the adaptive immune system. In addition, strong evidence for the contribution of Th2.