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.
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 CDpatients 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/R702WNOD2 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: S Dionne; M R Calderon; J H White; B Memari; I Elimrani; B Adelson; C Piccirillo; E G Seidman Journal: Mucosal Immunol Date: 2014-04-30 Impact factor: 7.313
Authors: Michael F Cunningham; Neil G Docherty; J Calvin Coffey; John P Burke; P Ronan O'Connell Journal: World J Surg Date: 2010-07 Impact factor: 3.352
Authors: Dalin Li; Jean-Paul Achkar; Talin Haritunians; Jonathan P Jacobs; Ken Y Hui; Mauro D'Amato; Stephan Brand; Graham Radford-Smith; Jonas Halfvarson; Jan-Hendrik Niess; Subra Kugathasan; Carsten Büning; L Philip Schumm; Lambertus Klei; Ashwin Ananthakrishnan; Guy Aumais; Leonard Baidoo; Marla Dubinsky; Claudio Fiocchi; Jürgen Glas; Raquel Milgrom; Deborah D Proctor; Miguel Regueiro; Lisa A Simms; Joanne M Stempak; Stephan R Targan; Leif Törkvist; Yashoda Sharma; Bernie Devlin; James Borneman; Hakon Hakonarson; Ramnik J Xavier; Mark Daly; Steven R Brant; John D Rioux; Mark S Silverberg; Judy H Cho; Jonathan Braun; Dermot P B McGovern; Richard H Duerr Journal: Gastroenterology Date: 2016-08-01 Impact factor: 22.682