Source
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Oxford University, 65 Aspenlea Road, London, W6 8LH, U.K.
Abstract
OBJECTIVE:
Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets, however ˜50% do not respond to this approach. Targeting pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy. However, 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. Amongst these cells, tenascin-C expression is most highly induced in activated dendritic cells, prompting us to examine its role in this cell type.
METHODS:
We systematically compared the phenotype of dendritic cells isolated from wild type mice or mice with a targeted deletion in tenascin-C by assessing cell maturation, cytokine synthesis and T cell polarization.
RESULTS:
Dendritic cells derived from tenascin-C null mice exhibit no defects in maturation; induction of MHC II and the co-stimulatory molecules CD40 and CD86 is unimpaired. However, dendritic cells that do not express tenascin-C produce lower levels of inflammatory cytokines than cells from wild type mice and exhibit specific defects in Th17 cell polarization. Moreover, tenascin-C null mice display ablated IL-17 levels in the joint during experimental arthritis.
CONCLUSIONS:
These data demonstrate that tenascin-C is important in dendritic cell-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.
Copyright © 2012 by the American College of Rheumatology.