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Science 4 February 2005:
Vol. 307. no. 5710, pp. 731 - 734
DOI: 10.1126/science.1104911
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Reports

Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract

Koichi S. Kobayashi,1* Mathias Chamaillard,3,4 Yasunori Ogura,1 Octavian Henegariu,1 Naohiro Inohara,3 Gabriel Nuñez,3,4{dagger} Richard A. Flavell1,2{dagger}{ddagger}

The gene encoding the Nod2 protein is frequently mutated in Crohn's disease (CD) patients, although the physiological function of Nod2 in the intestine remains elusive. Here we show that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. These animals are susceptible to bacterial infection via the oral route but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal anti-microbial peptides, known as cryptdins. The Nod2 protein is thus a critical regulator of bacterial immunity within the intestine, providing a possible mechanism for Nod2 mutations in CD.

1 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
2 The Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
3 Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4 Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.

* Present address: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: richard.flavell{at}yale.edu

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Am J Physiol Gastrointest Liver Physiol 290, G1157-G1163
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Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination.
E. Holler, G. Rogler, J. Brenmoehl, J. Hahn, H. Herfarth, H. Greinix, A. M. Dickinson, G. Socie, D. Wolff, G. Fischer, et al. (2006)
Blood 107, 4189-4193
   Abstract »    Full Text »    PDF »
IFN-{gamma} Enhances Production of Nitric Oxide from Macrophages via a Mechanism That Depends on Nucleotide Oligomerization Domain-2..
S. Totemeyer, M. Sheppard, A. Lloyd, D. Roper, C. Dowson, D. Underhill, P. Murray, D. Maskell, and C. Bryant (2006)
J. Immunol. 176, 4804-4810
   Abstract »    Full Text »    PDF »
The Front Line of Enteric Host Defense against Unwelcome Intrusion of Harmful Microorganisms: Mucins, Antimicrobial Peptides, and Microbiota.
V. Lievin-Le Moal and A. L. Servin (2006)
Clin. Microbiol. Rev. 19, 315-337
   Abstract »    Full Text »    PDF »
NF-{kappa}B-Inducing Kinase Regulates Selected Gene Expression in the Nod2 Signaling Pathway.
Q. Pan, V. Kravchenko, A. Katz, S. Huang, M. Ii, J. C. Mathison, K. Kobayashi, R. A. Flavell, R. D. Schreiber, D. Goeddel, et al. (2006)
Infect. Immun. 74, 2121-2127
   Abstract »    Full Text »    PDF »
Invited review: MDP and other muropeptides direct and synergistic effects on the immune system.
S. Traub, S. von Aulock, T. Hartung, and C. Hermann (2006)
Innate Immunity 12, 69-85
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Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation.
M. Kramer, M. G. Netea, D. J. de Jong, B. J. Kullberg, and G. J. Adema (2006)
J. Leukoc. Biol. 79, 860-866
   Abstract »    Full Text »    PDF »
Slipping the barrier: how variants in CARD15 could alter permeability of the intestinal wall and population health.
S Schreiber (2006)
Gut 55, 308-309
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Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?.
S Buhner, C Buning, J Genschel, K Kling, D Herrmann, A Dignass, I Kuechler, S Krueger, H H-J Schmidt, and H Lochs (2006)
Gut 55, 342-347
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Nod1-dependent control of tumor growth.
J. da Silva Correia, Y. Miranda, N. Austin-Brown, J. Hsu, J. Mathison, R. Xiang, H. Zhou, Q. Li, J. Han, and R. J. Ulevitch (2006)
PNAS 103, 1840-1845
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Identification and Functional Characterization of Three Chicken Cathelicidins with Potent Antimicrobial Activity.
Y. Xiao, Y. Cai, Y. R. Bommineni, S. C. Fernando, O. Prakash, S. E. Gilliland, and G. Zhang (2006)
J. Biol. Chem. 281, 2858-2867
   Abstract »    Full Text »    PDF »
Whipple's Disease: a Macrophage Disease.
B. Desnues, M. Ihrig, D. Raoult, and J.-L. Mege (2006)
Clin. Vaccine Immunol. 13, 170-178
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Layers of mutualism with commensal bacteria protect us from intestinal inflammation.
C Mueller and A J Macpherson (2006)
Gut 55, 276-284
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