Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori.

Rad, R; Brenner, L; Krug, A; Voland, P; Mages, J; Lang, R; Schwendy, S; Reindl, W; Dossumbekova, A; Ballhorn, W; Wagner, H; Schmid, RM; Bauer, S; Prinz, C

doi:10.1053/j.gastro.2007.04.071

Benutzer: Gast

2007

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Titel:: Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori.
Dokumenttyp:: Journal Article; Research Support, Non-U.S. Gov't
Autor(en):: Rad, R; Brenner, L; Krug, A; Voland, P; Mages, J; Lang, R; Schwendy, S; Reindl, W; Dossumbekova, A; Ballhorn, W; Wagner, H; Schmid, RM; Bauer, S; Prinz, C
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-1R(-/-), and IL-18(-/-) mice responded to H pylori with secretion of proinflammatory cytokines and up-regulation of major histocompatibility complex II and costimulatory molecules. In Myd88(-/-) 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 Myd88(-/-) 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 Myd88(-/-) 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.
Zeitschriftentitel:: Gastroenterology
Jahr:: 2007
Band / Volume:: 133
Heft / Issue:: 1
Seitenangaben Beitrag:: 150-163.e3
Sprache:: eng
Volltext / DOI:: doi:10.1053/j.gastro.2007.04.071
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/17631139
Print-ISSN:: 0016-5085
TUM Einrichtung:: II. Medizinische Klinik und Poliklinik (Gastroenterologie); Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Innere Medizin II, Gastroenterologie (Prof. Schmid)2007

mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Preclinical Medicine Institut für Medizinische Mikrobiologie, Immunologie und Hygiene (Prof. Busch)2007