Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.
Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.
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DOI：
10.1084/jem.20031763
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发表时间：
2004-12-06
期刊：
影响因子：
--
通讯作者：
Witztum JL
中科院分区：
文献类型：
--
作者：
Chang MK;Binder CJ;Miller YI;Subbanagounder G;Silverman GJ;Berliner JA;Witztum JL
低密度脂蛋白（LDL）的氧化产生多种具有免疫原性和促炎作用的氧化修饰脂质以及脂蛋白加合物，进而促进动脉粥样硬化的形成。通过氧化特异性单克隆抗体的结合测定，发生凋亡的细胞在其表面膜上也显示出氧化部分。在本文中，我们通过质谱分析证明，与活细胞相比，发生凋亡的细胞的膜中含有更高水平的具有生物活性的氧化磷脂（OxPLs）。事实上，用同基因凋亡细胞免疫小鼠可诱导针对氧化LDL的各种氧化特异性表位（包括含磷酰胆碱的OxPLs）的高自身抗体滴度，而用活的胸腺细胞、原发性坏死胸腺细胞或磷酸盐缓冲液免疫则不会。相应地，这些抗血清通过识别氧化特异性表位特异性地结合凋亡细胞。此外，来自用凋亡细胞免疫的小鼠的脾细胞培养物自发释放出显著水平的辅助性T细胞（Th）1和Th2细胞因子，而来自对照组的脾细胞仅产生低水平的细胞因子。最后，我们证明凋亡细胞的OxPLs激活内皮细胞以诱导单核细胞黏附，这种促炎反应可被针对氧化磷脂酰胆碱的特异性抗体所阻断。这些结果表明，凋亡细胞死亡产生氧化修饰部分，其可通过单核细胞 - 内皮细胞相互作用招募单核细胞，从而诱导自身免疫反应和局部炎症反应。
Oxidation of low density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. In the present paper, we demonstrated by mass spectrometry that in comparison with viable cells, membranes of cells undergoing apoptosis contain increased levels of biologically active oxidized phospholipids (OxPLs). Indeed, immunization of mice with syngeneic apoptotic cells induced high autoantibody titers to various oxidation-specific epitopes of oxidized LDL, including OxPLs containing phosphorylcholine, whereas immunization with viable thymocytes, primary necrotic thymocytes, or phosphate-buffered saline did not. Reciprocally, these antisera specifically bound to apoptotic cells through the recognition of oxidation-specific epitopes. Moreover, splenocyte cultures from mice immunized with apoptotic cells spontaneously released significant levels of T helper cell (Th) 1 and Th2 cytokines, whereas splenocytes from controls yielded only low levels. Finally, we demonstrated that the OxPLs of apoptotic cells activated endothelial cells to induce monocyte adhesion, a proinflammatory response that was abrogated by an antibody specific to oxidized phosphatidylcholine. These results suggest that apoptotic cell death generates oxidatively modified moieties, which can induce autoimmune responses and a local inflammatory response by recruiting monocytes via monocyte–endothelial cell interaction.
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影响因子：
4.4
作者：
Cocca, BA;Cline, AM;Radic, MZ
通讯作者：
Radic, MZ
影响因子：
7.4
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Witztum, JL
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作者：
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通讯作者：
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