title: Monocyte-derived dendritic cells from Crohn patients show differential NOD2/CARD15-dependent immune responses to bacteria.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salucci
authors.forename: Monica
authors.initials: M
authors.lastname: Rimoldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Penati
authors.forename: Gianluca M
authors.initials: GM
authors.lastname: Sampietro
authors.forename: Marjan Maria
authors.initials: MM
authors.lastname: van Duist
authors.forename: Gianluca
authors.initials: G
authors.lastname: Matteoli
authors.forename: Simone
authors.initials: S
authors.lastname: Saibeni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.forename: Sandro
authors.initials: S
authors.lastname: Ardizzone
authors.forename: Gabriele Bianchi
authors.initials: GB
authors.lastname: Porro
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
mesh_terms: 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
chemical_list: D016207:Cytokines; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein