| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Lymphocyte development, selection, and education are strictly controlled to prevent autoimmunity, with potentially autoreactive cells being removed by programmed cell death (called apoptosis). Dysregulation of apoptosis is a central defect in diverse marine autoimmune diseases. In murine models of autoimmune lupus and human autoimmune disease, for example, mutations in Fas/Apo-1 (CD95) or in its ligand (FasL) have been identified and shown to render lymphoid cells resistant to apoptosis. In contrast, select lymphoid subpopulations of mice with autoimmune diabetes manifest an increased susceptibility to apoptosis as a result of impaired activation of Large Multifunctional Protease-2 (LMP2), which is an essential subunit for the biological function of the immuno-proteasome, and can normally protects cells against Tumor Necrosis Factor-α (TNF-α)-induced apoptosis. It already demonstrated that LMP2 expression was markedly induced by IFN-γ stimulation.
Given the interest in IFN-γ as a Th1 activator and crucial role of Tap1/Lmp2 genes in antigen processing, here we studied the regulation of Tap1/Lmp2 genes in the murine system. Although there is a high homology between the Tap1/Lmp2 human and murine promoters, in the latter, JAK1 and IRF-1 are necessary to control the IFN-γ-induced gene expression. Although no specific genetic defects have been identified in most common forms of human autoimmune disease, functional assays consistently demonstrate heightened apoptosis attributable to multiple death signaling pathways.
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