A role of macrophages on antiphospholipid syndrome : antigen presenting and mechanisms on thrombosis

动脉内膜低密度脂蛋白(LDL)的氧化修饰参与动脉粥样硬化病变的发生和发展。抗磷脂综合征(APS)是一种自身免疫性疾病，可导致自身抗体介导的血栓形成。我们最近发现，APS衍生的免疫球蛋白与氧化型低密度脂蛋白(OxLDL)和β2-糖蛋白I(β2GPI)被巨噬细胞摄取并形成泡沫细胞。在本研究中，我们首先分析了oxLDL与β2GPI之间的相互作用，并确定了与β2GPI结合的oxLDL衍生的脂质配体(氧化脂)。然后，研究了β2GPI与巨噬细胞、树突状细胞等抗原提呈细胞的结合及其与β2GPI特异性T细胞的抗原提呈之间的关系。进一步研究了来自高脂血症小鼠和人的免疫球蛋白M天然抗体对巨噬细胞体外摄取氧化低密度脂蛋白的影响，并与β2GPI单独加入培养物时没有观察到抗原呈递，而与含有带负电荷的磷脂或来自氧化低密度脂蛋白的β2GPI特异性配体的脂质体一起作用。然而，β2GPI与巨噬细胞的结合与β2GPI特异性T细胞增殖(即抗原提呈)之间没有很好的相关性。巨噬细胞摄取与β2GPI相关的脂类，可能通过转运途径调节抗原的加工和提呈。与Ig G抗β2GPI自身抗体不同，Ig M抗oxLDL天然抗体可阻止巨噬细胞摄取oxLDL。巨噬细胞具有双重重要作用，即不仅参与脂类代谢，而且还参与抗原递呈。在未来的研究中，阐明巨噬细胞在自然免疫和自身免疫中的双重作用是非常重要的。

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.