(Taken from the application): Activation-induced cell death (AICD)in T cells is the major mechanism for peripheral tolerance. Repeated stimulation of T cells via their antigen receptor (TCR) induces co-expression of Fas and Fas ligand (FasL) on the surface of T cells and the Fas-FasL interaction leads to the """"""""suicide"""""""" or """"""""fratricide"""""""" of T cells. Plate-bound (surface-immobilized) anti-TCR antibody (e.g., anti-CD3 antibody) can mimic (auto)antigen-mediated T cell activation and AICD, and is a useful tool to study intracellular signaling mechanisms in T cells in vitro. Proteoglycan-induced arthritis is a novel autoimmune murine model induced by systemic immunization of BALB/c mice with cartilage proteoglycans. The development of the disease is based upon cross-reactive immune responses between the immunizing human and mouse (self) cartilage proteoglycans in genetically susceptible BALB/c mice. In this autoimmune arthritis model, an aberrant proliferation of peripheral CD4+ T cells was found in vitro in response to TCR stimulation. The hyper-proliferation of CD4+ T cells was associated with low levels of AICD and an unexpectedly high ratio of IFN-y, to IL-4 in arthritic mice. These observations together suggest that Th1 cells from arthritic mice may be resistant to AICD. The overall hypothesis of this proposal is that a defect(s) in the Fas-mediated signaling pathway lead to a deficiency in peripheral deletion of autoreactive Th1 type cells. As a result, autoreactlve Th1 cells accumulate in the periphery, leading to the breakdown of self-tolerance, and provoking inflammation in synovial joints by an antigen-driven mechanism. In this proposal, we will investigate whether and how defects in the intracellular regulators (FLIP, Bcl-2, and cell cycle modulators) of Fas-mediated signaling pathway results in impaired AICD of CD4+ T cells in proteoglycan-induced arthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Research Grants (R03)
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Special Emphasis Panel (ZAR1-TLB-B (O2))
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Gretz, Elizabeth
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Rush University Medical Center
United States
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