The candidate, Dr. Fei F. Shih, is a faculty member in the Rheumatology Division, Department of Pediatrics at Washington University. Dr. Shih has a long standing interest in autoimmune diseases. Her ultimate goal is to become an independent investigator in the field of autoimmunity and engage in translational research to apply her bench research to patient care. To achieve this goal she is examining T cell autoimmunity in KRN mice, a murine model of rheumatoid arthritis. Thymic deletion is the major mechanism whereby autoreactive T cells are eliminated from the functional cell repertoire. In KRN mice, incomplete deletion of KRN T cells with specificity for the ubiquitous self-antigen glucose-6-phosphate-isomerase (GPI) resulted in their activation and arthritis through provision of T cell help to anti-GPI B cells. Transgenic expression of a KRN TCR agonist under the MHC II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double transgenic mice succumbed to systemic autoimmunity with multi-organ inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by co-transfer of CD4+CD25+ Tregs. This proposal employs a two-prong approach to elucidate the mechanisms whereby systemic T cell autoreactivity can result in diverse disease phenotype from joint centered synovitis to a fulminant multi-organ inflammation.
Specific Aim 1 investigates the role of Tregs in the trafficking, growth, and the acquisition of effector function by pathogenic T cells.
Specific Aim 2 interrogates the capacity of different antigen presenting cells (under steady state and during inflammation) to present GPI and how this will affect the initiation and propagation of disease in KRN mice.
| Yi Qian; Jing Pan; Xiaodong Zhou et al. (2010) Contaminated heparin-affected patient plasmas are associated with activated contact systems. Clin Appl Thromb Hemost 16:261-5 |
| Monte, Kristen; Wilson, Christina; Shih, Fei F (2008) Increased number and function of FoxP3 regulatory T cells during experimental arthritis. Arthritis Rheum 58:3730-41 |
| Shih, Fei F; Racz, Jennifer; Allen, Paul M (2006) Differential MHC class II presentation of a pathogenic autoantigen during health and disease. J Immunol 176:3438-48 |
