The work was completed at the Kennedy Institute of Rheumatology when it was a division of Imperial College London; the Institute became a division of the University of Oxford on August 1, 2011.
Endogenous activation of adaptive immunity: Tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease†
Version of Record online: 26 JUN 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 7, pages 2179–2190, July 2012
How to Cite
Ruhmann, M., Piccinini, A. M., Kong, P. L. and Midwood, K. S. (2012), Endogenous activation of adaptive immunity: Tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease. Arthritis & Rheumatism, 64: 2179–2190. doi: 10.1002/art.34401
- Issue online: 26 JUN 2012
- Version of Record online: 26 JUN 2012
- Accepted manuscript online: 24 JAN 2012 03:52PM EST
- Manuscript Accepted: 19 JAN 2012
- Manuscript Received: 12 AUG 2011
- Kennedy Institute of Rheumatology Trust
- Arthritis Research UK
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.
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.
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.
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.