In vivo induction of mucosal damage and cell death by p31-43 gliadin

ARAYA ROMINA; DR. FERNANDO CHIRDO; PAULA CARASI; ELENA F. VERDU; MARÍA FLORENCIA GÓMEZ CASTRO; ALLAN MOWAT

copenhagen

Congreso; 10th European Mucosal Immunology Group Meeting; 2016

European Mucosal Immunology Group

Celiac disease (CD) is an enteropathy triggered by gluten in genetically susceptible individuals. A gluten specific T-cell response that requires the presence of HLA-DQ2/DQ8 genotype, and innate immune mechanisms participate in CD pathophysiology. We recently reported that intraluminal p31-43, a gliadin peptide resistant to gastrointestinal enzymes, induces innate immune activation and intestinal damage in C57BL/6 mice. The underlying pathways remain unclear.We aim to study the signalling pathways and mucosal changes induced by intraluminal p31-43 in C57Bl/6, IFNαR-/-, MyD88-/- and C3H-HeJ mice.Evaluation of villus/crypt ratio and number of intraepithelial lymphocytes in small intestinal sections showed severe mucosal damage in p31-43 treated mice but not in mice receiving PBS or a control peptide. Inflammation and mucosal changes were dependent on MyD88 and type I IFNs, but not TLR4. TUNEL reaction showed increased cell death in the mucosa, accompanied by higher (Bax/Bcl2 ratio) proapoptotic index in p31-43 treated mice. Flow cytometry analysis of intestinal epithelial cells isolated from p31-43 treated mice, showed increased number of AnnexinV+/propidium iodide+ cells.In conclusion, p31-43 activates innate immunity in intestinal mucosa leading to mucosal damage and cell death. P31-43 may induce similar pathways in human small intestine and play a role in CD pathogenesis.