Salant D J, Belok S, Madaio M P, Couser W G
J Clin Invest. 1980 Dec;66(6):1339-50. doi: 10.1172/JCI109987.
The only established role for complement in mediating immunologic renal disease involves elaboration of leukochemotactic factors and neutrophil-dependent glomerular injury. In the passive Heymann nephritis (PHN) model of experimental membranous nephropathy, rats injected with sheep antibody to rat proximal tubular brush border antigen (Fx1A) form subepithelial deposits of sheep IgG and rat complement (C3), and develop heavy proteinuria after 5 d without glomerular inflammatory changes. To study the role of complement in mediating proteinuria in PHN, 16 rats were treated daily with cobra venom factor from before antibody injection to maintain C3 levels at < 10% of pretreatment values and compared to 16 untreated controls. Proteinuria at 5 d was abolished in C3-depleted rats (4 +/- 1, controls 70 +/- 15 mg/d, P < 0.001), although renal deposition of 125I-labeled antibody ws the same in both groups (188 +/- 35 vs. 191 +/- 22 microgram IgG/2 kidneys, P > 0.5). Nephritogenic doses of both the noncomplement-fixing F(ab')2 portion and the gamma 2 subclass of anti-Fx1A IgG produced subepithelial deposits of immunoglobulin without C3, but proteinuria did not occur despite glomerular deposition of up to 70 microgram/2 kidneys of gamma 2. However, glomerular deposition of as little as 60 microgram of gamma 1 produced C3 fixation in vivo and heavy proteinuria. No neutrophil exudate could be detected histologically in PHN from the time of antibody injection through development of proteinuria. Proteinuria in five PHN rats depleted of neutrophils to < 200/mm3 with antineutrophil serum was not reduced compared to six controls with normal neutrophil counts (34 +/- 9.6 vs. 25 +/- 10.4 mg/d, P > 0.5). These results demonstrate that proteinuria in the PHN model of membranous nephropathy is complement-dependent and strongly suggest a neutrophil-independent mechanism. Thus a new role for the complement system in mediating immunologic glomerular injury is identified.
补体在介导免疫性肾病中唯一已确定的作用涉及白细胞趋化因子的产生以及中性粒细胞依赖性肾小球损伤。在实验性膜性肾病的被动海曼肾炎（PHN）模型中，注射抗大鼠近端肾小管刷状缘抗原（Fx1A）的绵羊抗体的大鼠形成绵羊IgG和大鼠补体（C3）的上皮下沉积物，并在5天后出现大量蛋白尿，而无肾小球炎症变化。为了研究补体在介导PHN蛋白尿中的作用，16只大鼠在注射抗体前每天用眼镜蛇毒因子治疗，以使C3水平维持在预处理值的<10%，并与16只未治疗的对照大鼠进行比较。C3耗竭的大鼠在5天时蛋白尿消失（4±1，对照组70±15mg/d，P<0.001），尽管两组中125I标记抗体的肾沉积相同（188±35对191±22μg IgG/2个肾脏，P>0.5）。非补体结合的F(ab')2部分和抗Fx1A IgG的γ2亚类的致肾炎剂量产生了无C3的免疫球蛋白上皮下沉积物，但尽管γ2在肾小球沉积量高达70μg/2个肾脏，蛋白尿并未发生。然而，低至60μg的γ1在体内的肾小球沉积会导致C3固定和大量蛋白尿。从注射抗体到蛋白尿出现的这段时间内，在PHN中组织学上未检测到中性粒细胞渗出。与6只中性粒细胞计数正常的对照大鼠相比，用抗中性粒细胞血清将5只PHN大鼠的中性粒细胞耗竭至<200/mm3后，蛋白尿并未减少（34±9.6对25±10.4mg/d，P>0.5）。这些结果表明，膜性肾病PHN模型中的蛋白尿是补体依赖性的，并强烈提示存在一种中性粒细胞非依赖性机制。因此，确定了补体系统在介导免疫性肾小球损伤中的新作用。
