Generation of C5a in the absence of C3: a new complement activation pathway
Generation of C5a in the absence of C3: a new complement activation pathway
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DOI：
10.1038/nm1419
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发表时间：
2006-06-01
期刊：
影响因子：
82.9
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Huber-Lang, Markus;Sarma, J. Vidya;Ward, Peter A.
补体介导的人体组织损伤发生在免疫复合物沉积时，如自身免疫性疾病和急性呼吸窘迫综合征。IgG免疫复合物沉积后，野生型和C3（-/-）小鼠的急性肺部炎症损伤具有相同的强度，并且是C5 a依赖性的，但Hc（-/-）小鼠（Hc编码C5）的损伤大大减弱。在抗凝血酶III（ATIII）或水蛭素的存在下，C3（-/-）小鼠的肺部损伤和这些小鼠支气管肺泡灌洗（BAL）液中的C5 a水平大大降低，但在经过类似处理的C3（+/+）小鼠中并未降低。与C3（+/+）小鼠血浆相比，C3（-/-）小鼠血浆中的凝血酶活性水平高3倍。与C3（+/+）小鼠相比，C3（-/-）小鼠肝脏中F2 mRNA（编码凝血酶原）以及凝血酶原和凝血酶蛋白的水平更高。使用来自C3（+/+）或C3（-/-）小鼠的血浆产生有效的固相C5转化酶。人C5与凝血酶孵育产生具有生物活性的C5 a。这些数据表明，在C3基因缺失的情况下，凝血酶替代了C3依赖性C5转化酶。补体和凝血途径之间的这种联系可能代表了一种新的补体激活途径。
Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3(-/-) mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc(-/-) mice ( Hc encodes C5). Injury in lungs of C3(-/-) mice and C5a levels in bronchoalveolar lavage ( BAL) fluids from these mice were greatly reduced in the presence of antithrombin III ( ATIII) or hirudin but were not reduced in similarly treated C3(+/+) mice. Plasma from C3(-/-) mice contained threefold higher levels of thrombin activity compared to plasma from C3(+/+) mice. There were higher levels of F2 mRNA ( encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3(-/-) mice compared to C3(+/+) mice. A potent solid- phase C5 convertase was generated using plasma from either C3(+/+) or C3(-/-) mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.