03019nas a2200517   4500000000100000008004100001260005300042653001700095653001800112653002500130653001400155653002000169653003700189653003800226653003000264653003100294653005300325653001100378653001700389653001200406653001200418653004400430653003500474653004400509653003300553653001900586653006400605100001300669700001500682700001500697700001100712700001200723700001300735700001900748700001200767700001000779700001400789700001000803700001200813700001400825245008700839300001100926490000700937520154300944022001402487       2012                            d  c2012 Mar 25bNature Publishing CompanyaNew York10aAntigens, CD10aCD11b Antigen10aCell Differentiation10aCytokines10aDendritic Cells10aDose-Response Relationship, Drug10aEnzyme-Linked Immunosorbent Assay10aGene Expression Profiling10aGene Expression Regulation10aGranulocyte-Macrophage Colony-Stimulating Factor10aHumans10aInterleukins10aleprosy10aLigands10aMacrophage Migration-Inhibitory Factors10aNod2 Signaling Adaptor Protein10aOligonucleotide Array Sequence Analysis10aPrincipal Component Analysis10aRNA, Messenger10aReceptors, Granulocyte-Macrophage Colony-Stimulating Factor1 aSchenk M1 aKrutzik SR1 aSieling PA1 aLee DJ1 aTeles R1 aOchoa MT1 aKomisopoulou E1 aSarno E1 aRea T1 aGraeber T1 aKim S1 aCheng G1 aModlin RL00aNOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy.  a555-630 v183 a<p>It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.</p>  a1546-170X