TY - JOUR
T1 - A deregulated immune response to gliadin causes a decreased villus height in DQ8 transgenic mice
AU - D'Arienzo, Rossana
AU - Stefanile, Rosita
AU - Maurano, Francesco
AU - Luongo, Diomira
AU - Bergamo, Paolo
AU - Mazzarella, Giuseppe
AU - Troncone, Riccardo
AU - Auricchio, Salvatore
AU - David, Chella
AU - Rossi, Mauro
PY - 2009/12
Y1 - 2009/12
N2 - Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-γ secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling.
AB - Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-γ secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling.
KW - Inflammation
KW - Mucosa
KW - T cells
KW - Transgenic mice
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U2 - 10.1002/eji.200839161
DO - 10.1002/eji.200839161
M3 - Article
C2 - 19795413
AN - SCOPUS:73249118020
SN - 0014-2980
VL - 39
SP - 3552
EP - 3561
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 12
ER -