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117?Allergy is an Epithelial Barrier Disease.

ABSTRACT: BackgroundThe purpose of this study is to explore the role of epithelium in acute allergic diseases.MethodsBirch pollen allergic patients and healthy control subjects were recruited. In vivo nasal pollen challenges were performed and nasal epithelial specimens were collected. A systems biology approach using a wealth of methods, including several microscopy techniques (light, confocal, immuno transmission electron [TEM]), transcriptomics (chips and massive parallel sequencing), mass spectrometry, immunohistology, in silico analyses were used.ResultsAlready 1 minute after the birch pollen perturbation Bet v 1 was found both on cell surfaces as well as within villae, in cytoplasm, in intracellular vesicles, and also in nuclei of epithelial cells in allergic patients, but not in the healthy individuals. Anti-Bet v 1 stainings in conjunctival biopsies supported a very rapid traffic through the epithelium in allergic patients, but not in healthy subjects. A striking specificity is observed when birch pollen allergic subjects were also challenged with timothy grass pollen and no entry of this pollen allergen Phl p 1 into epithelial cells was detected. While the specific transport mechanism for birch pollen remains unsolved the first hints of the role of caveolae in this have been obtained. In the double immunoTEM analyses caveolin 2, but not caveolin 1 or 3, was present on the conjunctival epithelial surface in the same clusters as Bet v 1. Transcriptomics indicated that the health epithelium displayed a strong immune response against pollen allergens while this response was absent in the epithelium of allergic patients.ConclusionsActive transport of allergens through the epithelium might be incorporated to the pathogenesis of allergy. It is possible that the healthy epithelium displays a strong immune response against pollen allergens and thus escapes from becoming allergic. If allergy turns out to be, at least in part, a result of epithelial hyposensitivity, it could have major consequences in the strategies of prevention and treatment of these diseases. Towards this end, a national allergy program has been launched in Finland, which changes the basic idea of trying to avoid allergens to the concept of natural exposure and tolerance.

SUBMITTER: Renkonen R

PROVIDER: S-EPMC3512654 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Project description:BackgroundLoss of intestinal epithelial barrier integrity is a critical component of Inflammatory Bowel Disease (IBD) pathogenesis. Co-expression regulation of ligand-receptor pairs in IBD mucosa has not been systematically studied. Targeting ligand-receptor pairs which are induced in IBD mucosa and function in intestinal epithelial barrier integrity may provide novel therapeutics for IBD.MethodsWe performed transcriptomic meta-analysis on public IBD datasets combined with cell surface protein-protein-interaction (PPI) databases. We explored primary human/mouse intestinal organoids and Caco-2 cells for expression and function studies of uPA-uPAR (prime hits from the meta-analysis). Epithelial barrier integrity was measured by Trans-Epithelial Electrical Resistance (TEER), FITC-Dextran permeability and tight junction assessment. Genetic (CRISPR, siRNA and KO mice) and pharmacological (small molecules, neutralizing antibody and peptide inhibitors) approaches were applied. Mice deficient of uPAR were studied using the Dextran Sulfate Sodium (DSS)-induced colitis model.FindingsThe IBD ligand-receptor meta-analysis led to the discovery of a coordinated upregulation of uPA and uPAR in IBD mucosa. Both genes were significantly upregulated during epithelial barrier breakdown in primary intestinal organoids and decreased during barrier formation. Genetic inhibition of uPAR or uPA, or pharmacologically blocking uPA-uPAR interaction protects against cytokine-induced barrier breakdown. Deficiency of uPAR in epithelial cells leads to enhanced EGF/EGFR signalling, a known regulator of epithelial homeostasis and repair. Mice deficient of uPAR display improved intestinal barrier function in vitro and during DSS-induced colitis in vivo.InterpretationOur findings suggest that blocking uPA-uPAR interaction via pharmacological agents protects the epithelial barrier from inflammation-induced damage, indicating a potential therapeutic target for IBD.FundingThe study was funded by Boehringer Ingelheim.

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117?Allergy is an Epithelial Barrier Disease.

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