Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells
Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells
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DOI：
10.1111/j.1365-2249.2009.03896.x
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发表时间：
2009-05-01
影响因子：
4.6
通讯作者：
Truedsson, L.
中科院分区：
文献类型：
--
作者：
Gullstrand, B.;Martensson, U.;Truedsson, L.
经典补体通路成分的遗传缺陷是系统性红斑狼疮（SLE）发展的强烈疾病易感因素，缺陷状态之间存在等级关系，与C1q缺陷的相关性最强。我们研究了不同补体途径在清除凋亡细胞方面的相对重要性。研究了单核细胞来源的巨噬细胞在补体缺乏个体血清中对标记的凋亡Jurkat细胞的吞噬作用，以及流式细胞术中C3在凋亡细胞上的沉积。缺乏C1q、C4、C2或C3的个体血清均显示吞噬能力下降。甘露糖结合凝集素（MBL）和替代途径不影响吞噬作用。值得注意的是，补体经典途径的成分，包括C1q，在清除凋亡细胞中同样重要。说明C3碎片的沉积具有重要意义；因此，我们研究了C3在凋亡细胞上的沉积。对缺乏mbl的C1q或因子D的实验证实了经典途径的优势。在低稀释条件下，缺乏C1q、C4或C2的血清支持C3片段沉积，显示了另一种途径激活。总之，我们发现补体介导的凋亡细胞的调理和吞噬作用，特别是那些发生继发性坏死的细胞，主要依赖于一个完整的经典途径。另一种途径不那么重要，但在某些情况下可能起作用。C1q并不比其他经典通路组分更重要，这表明除了清除凋亡细胞外，C1q还在SLE的其他发病过程中发挥作用。
Inherited deficiencies in components of the classical complement pathway are strong disease susceptibility factors for the development of systemic lupus erythematosus (SLE) and there is a hierarchy among deficiency states, the strongest association being with C1q deficiency. We investigated the relative importance of the different complement pathways regarding clearance of apoptotic cells. Phagocytosis of labelled apoptotic Jurkat cells by monocyte-derived macrophages in the presence of sera from individuals with complement deficiencies was studied, as well as C3 deposition on apoptotic cells using flow cytometry. Sera from individuals deficient in C1q, C4, C2 or C3 all showed decreased phagocytosis. Mannose binding lectin (MBL) and the alternative pathway did not influence phagocytosis. Notably, the components of the complement classical pathway, including C1q, were equally important in clearance of apoptotic cells. This indicates that deposition of C3 fragments is of major significance; we therefore studied C3 deposition on apoptotic cells. Experiments with MBL-deficient serum depleted of C1q or factor D confirmed the predominance of the classical pathway. At low dilution, sera deficient of C1q, C4 or C2 supported C3 fragment deposition demonstrating alternative pathway activation. In conclusion, we have found that complement-mediated opsonization and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. The alternative pathway is less important, but may play a role in some conditions. C1q was not more important than other classical pathway components, suggesting a role in additional pathogenetic processes in SLE other than clearance of apoptotic cells.