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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0805484

Received for publication August 30, 2005.
Revised October 30, 2005.
Accepted for publication November 21, 2005.

Article

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

Matthijs Kramer *, Mihai G. Netea {dagger}{ddagger}, Dirk J. de Jong {sect}, Bart Jan Kullberg {dagger}{ddagger}, and Gosse J. Adema *@

Departments of *Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, {sect}Gastroenterology and Hepatology, and {dagger}Medicine, {ddagger}Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, The Netherlands

@ To whom correspondence should be addressed. E-mail: g.adema{at}ncmls.ru.nl.


  Abstract

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 {alpha}, 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.

Key Words: human • cytokines • Toll-like receptor




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