Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
J Immunol. 2011 Sep 1;187(5):2101-11. doi: 10.4049/jimmunol.1003468. Epub 2011 Aug 3.
Defective clearance of apoptotic cells has been shown in systemic lupus erythematosus (SLE) and is postulated to enhance autoimmune responses by increasing access to intracellular autoantigens. Until now, research has emphasized inherited rather than acquired impairment of apoptotic cell engulfment in the pathogenesis of SLE. In this study, we confirm previous results that efficient removal of apoptotic cells (efferocytosis) is bolstered in the presence of wild-type mouse serum, through the C3 deposition on the apoptotic cell surface. In contrast, sera from three mouse models of SLE, Mer(KD), MRL(lpr), and New Zealand Black/WF1 did not support and in fact actively inhibited apoptotic cell uptake. IgG autoantibodies were responsible for the inhibition, through the blockade of C3 recognition by macrophages. Consistent with this, IgG removal reversed the inhibitory activity within autoimmune serum, and purified autoimmune IgG blocked both the detection of C3 on apoptotic cells and C3-dependent efferocytosis. Sera from SLE patients demonstrated elevated anti-C3b IgG that blocked detection of C3 on apoptotic cells, activity that was not found in healthy controls or patients with rheumatoid arthritis, nor in mice prior to the onset of autoimmunity. We propose that the suppression of apoptotic cell disposal by Abs against deposited C3 may contribute to increasing severity and/or exacerbations in SLE.
凋亡细胞的清除功能缺陷已在系统性红斑狼疮（SLE）中得到证实，并被推测通过增加细胞内自身抗原的可及性来增强自身免疫反应。到目前为止，研究强调了在 SLE 发病机制中，凋亡细胞吞噬作用的遗传性缺陷，而不是获得性缺陷。在这项研究中，我们证实了先前的结果，即在存在野生型小鼠血清的情况下，通过凋亡细胞表面 C3 的沉积，有效清除凋亡细胞（吞噬作用）得到增强。相比之下，来自三种 SLE 小鼠模型 Mer(KD)、MRL(lpr)和新西兰黑/WF1 的血清既不能支持，实际上还积极抑制凋亡细胞摄取。IgG 自身抗体通过阻断巨噬细胞对 C3 的识别导致了抑制作用。与此一致的是，IgG 清除在自身免疫血清中逆转了抑制活性，而纯化的自身免疫 IgG 阻断了凋亡细胞上 C3 的检测和 C3 依赖性吞噬作用。SLE 患者的血清表现出升高的抗 C3b IgG，可阻断凋亡细胞上 C3 的检测，而在健康对照者或类风湿关节炎患者以及自身免疫发生前的小鼠中均未发现这种活性。我们提出，针对沉积 C3 的 Abs 抑制凋亡细胞的清除可能导致 SLE 的严重程度增加和/或恶化。
