| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
The oxidative modification of low-density lipoprotein (LDL) in the intima of arteries contributes to the initiation and progression of atherosclerotic lesions. Antiphospholipid syndrome (APS) is an autoimmune disease that causes autoantibody-mediated thrombosis. We have recently found that APS derived-IgG immune complexes with oxidized LDL (oxLDL) and β2-glycoprotein I (β2GPI) were taken up by macrophages and results in forming foam cells.
In the present study, we fist analyzed interactions between oxLDL and β2GPI and identified the oxLDL-derived lipid ligands (oxidized lipids) for β2GPI binding. Then, relationship was studied between β2GPI binding to antigen presenting cells, such as macrophages and dendritic cells, and their antigen presenting to β2GPI-specific T cell cones. Further, effect of IgM natural antibodies from hyperlipidemic mice and human subjects on in vitro oxLDL uptake by macrophages were studied, as compared with APS-derived IgG autoantibodies.
Antigen presenting was not observed when β2GPI alone was added to culture but was together with liposomes containing negatively charged phospholipids or β2GPI-specific ligands from oxLDL. However, there were not good correlation between binding of β2GPI to macrophages and β2GPI-specific T cell proliferation (i.e., antigen presentation). Antigen processing and presentation may be regulated by trafficking way of lipids that were associated with β2GPI to be uptaken by macrophages. Not like IgG anti-β2GPI autoantibodies, IgM anti-oxLDL natural antibodies prevented oxLDL uptake by macrophages. Macrophages have dual important roles, i.e., not only on lipid metabolism but also on antigen presenting. In the future studies, it must be important to clarify the dual roles of macrophages on natural and autoimmunity.
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