Nucleosomes are exposed at the cell surface in apoptosis
Nucleosomes are exposed at the cell surface in apoptosis
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DOI：
10.4049/jimmunol.172.11.6692
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Monestier, M
中科院分区：
文献类型：
--
作者：
Radic, M;Marion, T;Monestier, M
凋亡细胞被认为是DNA、组蛋白和核蛋白复合体的来源，这些复合体推动系统性红斑狼疮自身抗体的产生。然而，凋亡细胞在免疫系统激活中的作用尚不清楚。为了探索可能启动或维持抗核自身抗体产生的相互作用，我们表征了一大组单克隆自身抗体与凋亡细胞的结合。抗DNA、单个核心组蛋白、组蛋白-DNA复合体或天然核小体核心颗粒的自身抗体在共聚焦显微镜下显示出一致和特定的结合模式。免疫反应表位在胞浆中检测到，并以caspase依赖的方式沿碎裂的核表面聚集。从质膜上出现的核碎片上的银-抗体复合体可以与抗同型反应的微粒结合。此外，针对核小体核心或其分子组成的自身抗体在诱导细胞凋亡后4h选择性地从胞浆中沉淀核心组蛋白和DNA的复合体。这些观察确定了核小体从细胞核释放及其暴露在细胞表面的不同步骤。此外，研究结果还表明，核小体在执行细胞凋亡、清除凋亡细胞和调节抗核自身抗体的产生中起着直接作用。
Apoptotic cells are considered the source of DNA, histones, and nucleoprotein complexes that drive the production of autoantibodies in systemic lupus erythematosus. However, the role of apoptotic cells in the activation of the immune system is not clear. To explore interactions that may initiate or sustain the production of anti-nuclear autoantibodies, we characterized the binding of a large panel of monoclonal autoantibodies to apoptotic cells. Autoantibodies to DNA, individual core histones, histone-DNA complexes, or the native nucleosome core particle revealed a consistent and specific binding pattern in confocal microscopy. Immunoreactive epitopes were detected in the cytoplasm and accumulated along the surface of the fragmenting nucleus in a caspase-dependent manner. Ag-Ab complexes on nuclear fragments that had emerged from the plasma membrane were accessible to anti-isotype-reactive microparticles. Moreover, autoantibodies specific for the nucleosome core or its molecular components selectively precipitated a complex of core histones and DNA from the cytosol at 4 h after induction of apoptosis. These observations identify distinct steps in the release of nucleosomes from the nucleus and their exposure at the cell surface. Furthermore, the results indicate a direct role for nucleosomes in the execution of apoptosis, clearance of apoptotic cells, and regulation of antinuclear autoantibody production.