AN INHERITED DEFICIENCY OF THE 3RD COMPONENT OF COMPLEMENT, C-3, IN GUINEA-PIGS
AN INHERITED DEFICIENCY OF THE 3RD COMPONENT OF COMPLEMENT, C-3, IN GUINEA-PIGS
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DOI：
10.1002/eji.1830160103
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发表时间：
1986-01-01
影响因子：
5.4
通讯作者：
BITTERSUERMANN, D
中科院分区：
文献类型：
--
作者：
BURGER, R;GORDON, J;BITTERSUERMANN, D
补体第三成分C3的遗传性缺乏在人类中很少发现。C3缺乏症与严重的细菌感染有关，揭示了C3通过经典或替代途径在补体激活中的核心作用。我们描述了一种新的遗传性C3缺乏症的应变2豚鼠。在补体依赖性、抗体介导的细胞毒性的标准试验中，这些动物的血清具有显著降低的裂解活性。在单个组分的功能试验中，组分C4、C2、C5和因子B、D和H的溶血活性在正常范围内。这些C3缺陷动物（C3 D）血清中的功能性C3滴度和类似的C3抗原活性平均仅为正常活性的5.7%。用豚鼠Ia抗原的同种抗血清或单克隆抗体对动物进行分型，发现C3 D动物具有近交系2豚鼠的主要组织相容性复合物单倍型（B.1，Ia.2，4）。C3缺陷与主要组织相容性复合体无关，此外，也与C3 a受体缺陷无关。通过酶联免疫吸附试验测定，C3 D动物的巨噬细胞和肝细胞合成和分泌C3的能力未受损。如125 I-放射性标记C3的血浆清除率所示，动物没有正常C3的高钙血症迹象。在ATP释放试验中，C3 D动物的血小板对纯化的C3 a刺激反应正常，而没有体内脱敏的迹象。可能故障在于其自身C3对蛋白水解的敏感性增强。然而，C3部分纯化的血浆中的C3 D动物或肝细胞分泌的十二烷基硫酸钠-聚丙烯酰胺凝胶电泳或免疫印迹显示没有明显的结构差异，纯化的正常C3。与正常或C4缺陷型血清相比，C3 D血清具有降低的杀菌活性。 尽管如此，动物显然是健康的，没有细菌感染频率增加的迹象。这些豚鼠提供了一种独特的模型，用于分析体内和体外C3的生物学功能，而不需要人工C3消耗程序及其所有已知和未知的副作用。
Hereditary deficiency of the third component of complement, C3, is found very seldom in the human. C3 deficiency is associated with severe bacterial infections revealing the central role of C3 in complement activation via the classical or alternative pathway. We describe a new hereditary C3 deficiency in strain 2 guinea pigs. Serum from these animals had a markedly reduced lytic activity in a standard assay for complement-dependent, antibody-mediated cytotoxicity. In functional assays of individual components, the hemolytic activity of the components C4, C2, C5 and of factors B, D and H was in the normal range. The functional C3 titer, and similarly C3 antigenic activity in the serum of these C3-deficient animals (C3D) was on average only 5.7% of normal activity. Typing the animals with alloantisera or monoclonal antibodies to guinea pig Ia-antigens revealed that the C3D animals had the major histcompatibility complex-haplotype of inbred strain 2 guinea pigs (B.1, Ia.2,4). The C3 defect is not linked to the major histocompatibility complex and, in addition, is not linked to a C3a receptor deficiency. Macrophages and hepatocytes of the C3D animals have an unimpaired capacity for synthesis and secretion of C3 as measured by enzyme-linked immunosorbent assay. There was no indication for hypercatabolism of normal C3 by the animals as shown by plasma clearance of 125I-radiolabeled C3. Thrombocytes of the C3D animals responded normally to stimulation with purified C3a in an ATP-release assay without an indication for a desensitization in vivo. Possibly the fault resides in an enhanced susceptibility of their own C3 to proteolysis. However, C3 partially purified from the plasma of the C3D animals or secreted by hepatocytes exhibited no obvious structural differences to purified normal C3 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis or in immunoblotting. The C3D serum had a reduced bactericidal activity compared to normal or to C4-deficient serum. Nevertheless, the animals are apparently healthy without an indication for increased frequency of bacterial infections. These guinea pigs provide an unique model for analysis of the biological functions of C3 in vivo and in vitro without the need for artificial C3-depletion procedures with all their known and unknown sideeffects.