CARD15/NOD2 is required for Peyer's patches homeostasis in mice.
BACKGROUND
CARD15/NOD2 mutations are associated with susceptibility to Crohn's Disease (CD) and Graft Versus Host Disease (GVHD). CD and GVHD are suspected to be related with the dysfunction of Peyer's patches (PP) and isolated lymphoid follicles (LFs). Using a new mouse model invalidated for Card15/Nod2 (KO), we thus analysed the impact of the gene in these lymphoid formations together with the development of experimental colitis.


RESULTS
At weeks 4, 12 and 52, the numbers of PPs and LFs were higher in KO mice while no difference was observed at birth. At weeks 4 and 12, the size and cellular composition of PPs were analysed by flow cytometry and immunohistochemistry. PPs of KO mice were larger with an increased proportion of M cells and CD4(+) T-cells. KO mice were also characterised by higher concentrations of TNFalpha, IFNgamma, IL12 and IL4 measured by ELISA. In contrast, little differences were found in the PP-free ileum and the spleen of KO mice. By using chamber experiments, we found that this PP phenotype is associated with an increased of both paracellular permeability and yeast/bacterial translocation. Finally, KO mice were more susceptible to the colitis induced by TNBS.


CONCLUSIONS
Card15/Nod2 deficiency induces an abnormal development and function of the PPs characterised by an exaggerated immune response and an increased permeability. These observations provide a comprehensive link between the molecular defect and the Human CARD15/NOD2 associated disorders: CD and GVHD.
Barreau
Frédérick
F
U843, INSERM, Paris, France; UMR-S843, Université Paris Diderot, Paris, France.
Meinzer
Ulrich
U
Chareyre
Fabrice
F
Berrebi
Dominique
D
Niwa-Kawakita
Michiko
M
Dussaillant
Monique
M
Foligne
Benoit
B
Ollendorff
Vincent
V
Heyman
Martine
M
Bonacorsi
Stéphane
S
Lesuffleur
Thecla
T
Sterkers
Ghislaine
G
Giovannini
Marco
M
Hugot
Jean-Pierre
JP
D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D010581:Peyer's Patches / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger