Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
3296765 | Gastroenterology | 2007 | 17 Pages |
Abstract
Background & Aims: Recognition of infection leads to induction of adaptive immunity through activation of antigen-presenting cells (APCs). Among APCs, dendritic cells (DCs) have the unique capacity to deliver antigens from the periphery to T cells in secondary lymphoid organs. Methods: We analyzed molecular mechanisms of the Helicobacter pylori-induced APC activation in vitro and investigated the influence of Myd88 signaling on the phenotype of adaptive immunity to H pylori in a murine infection model. Results: The adaptor protein Myd88 mediates Toll-like receptor (TLR), interleukin (IL)-1, and IL-18 signaling. DCs from wild-type, IL-1Râ/â, and IL-18â/â mice responded to H pylori with secretion of proinflammatory cytokines and up-regulation of major histocompatibility complex II and costimulatory molecules. In Myd88â/â DCs these processes were impaired profoundly, showing that TLR-dependent H pylori-sensing affects DC activation. Analysis of the H pylori-specific DC transcriptome revealed that large parts of the bacteria-induced transcriptional changes depended on Myd88 signaling, comprising numerous genes involved in crucial steps of immune regulation, such as DC maturation/differentiation, antigen uptake/presentation, and effector cell recruitment/activation. The impaired ability of Myd88â/â DCs, B cells, and macrophages to mount a proinflammatory response to H pylori in vitro was reflected in vivo by reduced gastric inflammation and increased bacterial colonization in Myd88-deficient mice. Furthermore, Helicobacter-specific IgG2c/IgG1 ratios were reduced in Myd88â/â animals, suggesting the involvement of the Myd88-dependent pathway in the instruction of adaptive immunity toward a T helper cell type 1 phenotype. Conclusions: A principal pathway by which DCs sense H pylori and become activated is the TLR-dependent signaling cascade. In vivo, Myd88 signaling affects adaptive immunity to the bacterium.
Keywords
myeloid differentiation factorAPCTLRGFPMYD88BMDCLPSTNFFACSMOITRIFantigen-presenting cellinterleukinEnzyme-linked immunosorbent assayELISAToll-like receptorDendritic cellBone marrow–derived dendritic cellT helper celltumor necrosis factorfluorescence-activated cell sorterlipopolysaccharideMHCmajor histocompatibility complexpolymerase chain reactionPCRgreen fluorescent proteinmultiplicity of infection
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Authors
Roland Rad, Lena Brenner, Anne Krug, Petra Voland, Jörg Mages, Roland Lang, Susanne Schwendy, Wolfgang Reindl, Anar Dossumbekova, Wibke Ballhorn, Hermann Wagner, Roland M. Schmid, Stefan Bauer, Christian Prinz,