Generation of multiple fluid-phase C3b:plasma protein complexes during complement activation: possible implications in C3 glomerulopathies.
Generation of multiple fluid-phase C3b:plasma protein complexes during complement activation: possible implications in C3 glomerulopathies.
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DOI：
10.4049/jimmunol.1302288
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发表时间：
2014-02-01
期刊：
影响因子：
--
通讯作者：
Kew RR
中科院分区：
文献类型：
--
作者：
Ramadass M;Ghebrehiwet B;Smith RJ;Kew RR
补体系统受到严格调节，以防止因意外激活而造成的组织损伤。 C3 裂解为 C3b 的关键步骤受到控制激活起始和程度的多种机制的调节。这项研究表明，C3b：血浆蛋白复合物在补体激活过程中在液相中形成。当在正常人血清或血浆中触发三种补体激活途径中的任何一种时，几种不同的血浆蛋白显示出离散的高分子 SDS 抗性条带。去除单个补体蛋白的血清表明，C3、因子 B 和 D 对于复合物的形成至关重要。 C3 中硫酯键的失活也阻止了复合物的形成。在体外，可以使用四种纯化蛋白生成复合物：C3、因子 B、因子 D、靶蛋白和 Mg2+，以允许 C3 转化酶形成。这些研究表明，复合物由血浆蛋白以 1:1 摩尔比共价结合到 C3b 组成； C3b 部分被因子 H 和 I 迅速降解。对致密沉积病 (DDD) 和 C3 肾小球肾炎 (C3GN) 患者血浆样本的分析表明，C3b：蛋白质复合物在 DDD 患者的血液中自发形成，在 C3GN 患者中自发形成，但在健康对照中则没有。这一发现支持了以下假设：这些 C3 肾小球病是液相补体失调性疾病。这些复合物通常可以作为一种被动机制来拦截 C3b 沉积在宿主细胞上。然而，液相 C3b: 蛋白质复合物的过度生成和/或清除缺陷可能会产生病理后果。
The complement system is tightly regulated to safeguard against tissue damage that results from unwanted activation. The key step of C3 cleavage to C3b is regulated by multiple mechanisms that control the initiation and extent of activation. This study demonstrated that C3b:plasma protein complexes form in the fluid-phase during complement activation. Several different plasma proteins displayed a discrete high molecular SDS-resistant band when any of the three complement activating pathways were triggered in normal human serum or plasma. Serum depleted of individual complement proteins revealed that C3, factors B and D were essential for complex formation. Inactivation of the thioester bond in C3 also prevented complex formation. In vitro, complexes could be generated using four purified proteins: C3, factor B, factor D, target protein and Mg2+ to allow C3 convertase formation. These studies showed that the complexes consisted of a plasma protein covalently bound to C3b in a 1:1 molar ratio; the C3b portion was rapidly degraded by factors H and I. Analysis of plasma samples from patients with dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) demonstrated that C3b:protein complexes form spontaneously in the blood of patients with DDD and to a lesser extent in C3GN patients, but not in healthy controls. This finding supports the underlying hypothesis that these C3 glomerulopathies are diseases of fluid-phase complement dysregulation. These complexes could normally function as a passive mechanism to intercept C3b from depositing on host cells. However, excessive generation and/or defective clearance of fluid-phase C3b:protein complexes may have pathological consequences.
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影响因子：
19.6
作者：
通讯作者：
--
影响因子：
5.9
作者：
CAMERON, JS;TURNER, DR;HICKS, J
通讯作者：
HICKS, J
DOI：
10.1016/0090-1229(92)90045-p
发表时间：
1992-01-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
FRANK, MM;BASTA, M;FRIES, LF
通讯作者：
FRIES, LF
影响因子：
4.4
作者：
Schwertz, R;Rother, U;Kirschfink, M
通讯作者：
Kirschfink, M
影响因子：
3.7
作者：
Alba-Domínguez M;López-Lera A;Garrido S;Nozal P;González-Granado I;Melero J;Soler-Palacín P;Cámara C;López-Trascasa M
通讯作者：
López-Trascasa M