Spondyloarthritis encompasses a group of inflammatory disorders with shared genetic risk factors and overlapping clinical features. Data from genome-wide association studies point toward a central role for IL-23 in spondyloarthritis pathogenesis. A recent report (Sherlock et al. Nature Medicine 2012) described a spondyloarthritis-like illness in mice induced by IL-23 overexpression in adult animals and identified a CD4-CD8- double negative T cell subset that mediated disease development by secreting IL-17A and IL- 22 in response to IL-23. The proposed project is built on the premise that the IL-23 minicircle-induced spondyloarthritis model has enormous potential for elucidating the pathogenesis of spondyloarthritis.
Specific Aim 1 analyzes factors controlling the development and function of the disease-mediating IL-23 receptor positive DN T cells. Using a panel of knockout mice we will test the hypothesis that these cells are MHC class I restricted ??TCR positive cells that may represent a link between HLA-B27 disease association, IL-23 and the development of spondyloarthritis. We will further explore the function of the transcription factors T-bet and Ahr in these cells.
In Specific Aim 2 we begin to interrogate the mechanism of osteoproliferation induced by the downstream mediator IL-22 and identify candidate pathways for future more detailed analysis.
The project utilizes a model of spondyloarthritis induced by overexpression of the cytokines IL-23 or IL-22 in adult mice to investigate spondyloarthritis disease mechanisms. We propose to characterize the IL-23 receptor-positive disease-mediating lymphocytes and explore the mechanisms of abnormal bone formation in this model.
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