title: Endogenous activation of adaptive immunity: tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease.
abstract: OBJECTIVE
  Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, ∼50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood. Tenascin-C is an arthritogenic extracellular matrix glycoprotein that is not expressed in healthy synovium but is elevated in the rheumatoid joint, where high levels are produced by myeloid cells. Among these cells, tenascin-C expression is most highly induced in activated dendritic cells (DCs). The aim of this study was to examine the role of tenascin-C in this cell type.
  
  
  METHODS
  We systematically compared the phenotype of DCs isolated from wild-type mice or mice with a targeted deletion of tenascin-C by assessing cell maturation, cytokine synthesis, and T cell polarization.
  
  
  RESULTS
  Dendritic cells derived from tenascin-C-null mice exhibited no defects in maturation; induction of the class II major histocompatibility complex and the costimulatory molecules CD40 and CD86 was unimpaired. Dendritic cells that did not express tenascin-C, however, produced lower levels of inflammatory cytokines than did cells from wild-type mice and exhibited specific defects in Th17 cell polarization. Moreover, tenascin-C-null mice displayed ablated levels of interleukin-17 in the joint during experimental arthritis.
  
  
  CONCLUSIONS
  These data demonstrate that tenascin-C is important in DC-mediated polarization of Th17 lymphocytes during inflammation and suggest a key role for this endogenous danger signal in driving adaptive immunity in erosive joint disease.
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Ruhmann
authors.forename: Anna M
authors.initials: AM
authors.lastname: Piccinini
authors.forename: Philip L
authors.initials: PL
authors.lastname: Kong
authors.forename: Kim S
authors.initials: KS
authors.lastname: Midwood
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D019063:Tenascin