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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
1R03AR066357-01A1
Application #
8825664
Study Section
Special Emphasis Panel (ZAR1-XZ (M1))
Program Officer
Mao, Su-Yau
Project Start
2014-09-12
Project End
2017-08-31
Budget Start
2014-09-12
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$74,908
Indirect Cost
$24,908
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115