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NOD2 mutation and mice: no Crohn's disease but many lessons to learn

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Many patients with ileal Crohn's disease, a chronic intestinal inflammation, carry mutations in the gene encoding NOD2 (CARD15), but the mechanistic details of how this mutation leads to disease are not fully understood. NOD2 is expressed in antigen-presenting cells and Paneth cells, which are secretory epithelial cells of the small intestine. Two complementary studies using genetically engineered murine models help to explain the association of NOD2 malfunction and mucosal disease. One study observes a dysregulation of proinflammatory responses, suggesting that the most common NOD2 mutation in humans results in a gain of function. The other study determined that NOD2-null mutations impair the Paneth-cell antimicrobial response, which is consistent with recent findings in humans. Together, these studies fuel optimism that new therapeutic directions might emerge to better treat this severe mucosal disease.

Section snippets

Dr Crohn, NOD2 and Crohn's disease of the small intestine

Dr Burrill B. Crohn practiced medicine at the Mount Sinai Hospital in New York City. In the famous JAMA article from 1932, he and his colleagues reported a mysterious small-intestinal disease [1], which is now known as Crohn's disease. In industrialized countries, this chronic intestinal inflammation affects ∼1 in 500 individuals. Crohn's disease is a heterogeneous disorder with different clinical phenotypes, and the main localizations of inflammation are the small-intestinal ileum and/or the

Mice with NOD2 knockout and loss of function

Kobayashi and colleagues [8] used a sophisticated approach: they generated mice deficient in the gene encoding Nod2. Surprisingly, these mice had no readily apparent phenotype; that is, no visible intestinal signs of spontaneous inflammation after six months of observation. The authors found that macrophages from the bone marrow of normal but not those of Nod2-knockout mice detected bacterial MDP. Thus, Nod2 deficiency rendered macrophages unresponsive to MDP [8]. Taken together, these findings

Mice with NOD2-frameshift mutation and gain of function

In the paper by Maeda et al. [9], the authors have developed mice with the most common mutant form of Nod2, which is identical to that found in many patients with ileal Crohn's disease [9]. To better understand the interplay between the Nod2 mutation and intestinal bacteria, the authors provoked a colonic exposure of inflammatory cells with commensal bacteria in these mutant mice by adding a chemical to their drinking water (dextran sodium sulfate) that injured their intestinal epithelial

Crohn's disease – intestinal bacteria at the center of disease

More than 70 years ago, Dr Crohn and his colleagues stated that the etiology of this inflammatory process is unknown, but the authors speculated that there could be an infectious genesis. Crohn et al. [1] also pointed out that the healthy intestine shows a remarkable resistance to infection and inflammatory lesions. ‘…but in some instances, however, following infection or injury, resitutio ad integram [back to normal] does not occur’. Even if only a small minority of experts would have agreed

Therapy and future directions

This view of Crohn's disease might provide the necessary rationale to find new therapeutic strategies that act at the mucosal bacterial interface. The study by Maeda et al. [9] supports two alternative therapeutic approaches. Blocking the inflammatory immune response by using an IL-1β-receptor blocker represents a common theme in the modern treatment of Crohn's disease. In the second approach, provided by antibiotic therapy, the absence of bacteria also protects Nod2-mutant mice from disease [9]

Concluding remarks

The papers by Kobayashi et al. [8] and Maeda et al. [9] provide new insights into the molecular details of how this mutation leads to inflammation in Crohn's disease and will hopefully help to open more therapeutic avenues in the future. In our opinion, the lack of mucosal defensins 7, 8, 10 and increased cytokine response 9, 11 represent the sequential pathogenetic mechanism of the disease and are not mutually exclusive. Nevertheless, a caveat is necessary: Crohn's disease in the mouse has not

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