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Title: The role of tenascin-C in dendritic cell functions and adaptive immunity in rheumatoid arthritis
Author: Ruhmann, Michaela
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic inflammation of the synovium. Both innate and adaptive immunity play a role in driving inflammation in RA, in particular, Th1 and Th17 cells are implicated in disease pathogenesis. Currently available RA treatments are not effective in a relatively large subset of RA patients, therefore new therapeutic strategies have to be found. Our group found that the extracellular matrix glycoprotein tenascin-C is an endogenous activator of Toll-like receptor 4 that induces cytokine synthesis in human synovial fibroblasts and macrophages. Elevated levels of tenascin-C are found in the RA joint, mainly produced by myeloid cells. Activated human dendritic cells (DCs) express high levels of tenascin-C. Thus, the aim of this study was to examine if tenascin-C plays a role in DC function and adaptive immunity in RA. I found that murine bone marrow-derived dendritic cells (BMDCs) express high levels of tenascin-C upon plating. I showed that BMDCs from tenascin-C null mice secrete significantly lower levels of pro-inflammatory cytokines, including TNF?, IL-6, KC and IP-10, upon lipopolysaccharide (LPS) stimulation than BMDCs from wild-type mice. I demonstrated that tenascin-C promotes BMDC cytokine synthesis on a post-transcriptional level. BMDCs from tenascin-C null mice also had a defect in Th17 cell polarization. In contrast, Th1, Th2 or Treg cell polarization was not impaired in BMDCs from tenascin-C null mice. Furthermore, I showed that tenascin-C null mice exhibit ablated expression levels of pro-inflammatory and Th17-related cytokines, including IL-17, IL-6, IL-1? and IL-23, in the joint during experimental arthritis, indicating that tenascin-C promotes a local cytokine environment favourable to Th17 differentiation. Together, my data indicate that tenascin-C serves as an important link between innate and adaptive immunity and that it plays a role in driving inflammation and adaptive immunity in erosive joint disease. Hence, tenascin-C may be a potential therapeutic target for the treatment of RA.
Supervisor: Midwood, Kim ; Horwood, Nikki Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available