Nod2 and Crohn's disease: many connected highways

In this issue of The Lancet, David van Heel and co-workers analyse the innate immunity driven by the mononuclear cells of patients with Crohn's disease. Using nanomolar concentrations of muramyldipeptide in an ex-vivo system, they report that pathways act synergistically for the nucleotide oligomerisation domain 2 (Nod2, also known as caspase-recruitment domain 15 or Card15) and toll-like receptor (TLR). Co-activation of these two pathways dramatically increased the production of proinflammatory chemokines. This observation argues for an integrated response of innate immunity. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's diseaseBoth NOD2 (CARD15) alleles are mutated in roughly 15% of patients with Crohn's disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFα or interleukin 1β, but strong interleukin-8 secretion. MDP also substantially upregulated secretion of TNFα and interleukin 1β induced by toll-like receptor ligands. These effects were abolished by the most common Crohn's NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. Full-Text PDF