Monocyte-derived dendritic cells from Crohn patients show differential NOD2/CARD15-dependent immune responses to bacteria.
BACKGROUND
Three common mutations in the NOD2/CARD15 gene are strongly associated with Crohn's disease (CD). NOD2 is an intracellular receptor of muramyl dipeptide (MDP), a component of peptidoglycan present in the cell wall of gram-positive (G+) and gram-negative (G-) bacteria.


METHODS
We generated monocyte-derived dendritic cells (MoDCs) from CD patients mutated or not for CARD15 (n = 53) or from healthy donors (n = 12) and analyzed their activation in response to live Salmonella typhimurium as a model of pathogenic G- bacteria.


RESULTS
MoDCs carrying the L1007fs mutation, although phenotypically activated by bacteria, produced a significantly reduced amount of tested cytokines. MoDCs carrying R702W or compound G908R/R702W NOD2 mutations displayed an increased basal level of IL-8 release. After a bacterial encounter, these cells were phenotypically activated and produced levels of cytokines similar to healthy controls. Interestingly, although L1007fs/WT mutations conferred reduced production of cytokines, including IL-12, these cells were perfectly capable of inducing T-cell polarization toward the Th1 phenotype.


CONCLUSIONS
NOD2 mutations affect the basal characteristics of MoDCs and their response to G- bacteria differently. MoDCs could be involved in CD onset because they have defects in releasing inflammatory cytokines and in polarizing T-cell responses.
Salucci
Valentina
V
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Rimoldi
Monica
M
Penati
Chiara
C
Sampietro
Gianluca M
GM
van Duist
Marjan Maria
MM
Matteoli
Gianluca
G
Saibeni
Simone
S
Vecchi
Maurizio
M
Ardizzone
Sandro
S
Porro
Gabriele Bianchi
GB
Rescigno
Maria
M
D000293:Adolescent; D000328:Adult; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D012486:Salmonella typhimurium / Q000276:immunology
D016207:Cytokines; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein