Impaired dendritic cell function in Crohn’s disease patients with NOD2 3020insC mutation

• Published in: Journal of leukocyte biology Vol. 79; no. 4; pp. 860 - 866
• Main Authors: Kramer, Matthijs, Netea, Mihai G., Jong, Dirk J., Kullberg, Bart Jan, Adema, Gosse J.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01-04-2006
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - pharmacology; Adult; Crohn Disease - genetics; Crohn Disease - immunology; cytokines; Cytokines - biosynthesis; Dendritic Cells - drug effects; Dendritic Cells - immunology; Female; human; Humans; Interleukin-10 - pharmacology; Intracellular Signaling Peptides and Proteins - genetics; Ligands; Male; Middle Aged; Mutation; Nod2 Signaling Adaptor Protein; Phenotype; Toll-Like Receptors - immunology; Toll‐like receptor
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0805484

The nucleotide oligomerization domain 2 (NOD2) 3020insC (NOD2fs) mutation increases susceptibility to Crohn’s disease (CD), but the mechanism remains controversial. Loss‐of‐function and gain‐of‐function phenotypes have been described as a result of NOD2fs. Here, we show that dendritic cells (DC) derived from CD patients homozygous for this mutation respond normally to purified Toll‐like receptor (TLR) ligands but fail to up‐regulate the costimulatory molecules CD80 and CD86 in response to the NOD2 ligand muramyl dipeptide (MDP). Moreover, they lack MDP‐induced enhancement of TLR‐mediated tumor necrosis factor α, interleukin (IL)‐12, and IL‐10 production, which is observed in control DC with intact NOD2. These data indicate that the NOD2fs mutation results in a loss‐of‐function phenotype in human myeloid DC and imply decreased immune regulation by IL‐10 as a possible mechanism for this mutation in CD.